Carboxylic acid amides, the preparation thereof and their use as medicaments

ABSTRACT

The present invention relates to new substituted carboxylic acid amides of general formula 
     
       
         
         
             
             
         
       
     
     wherein A, B and R 1  to R 5  are defined as in claim  1 , the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

FIELD OF THE INVENTION

The present invention relates to new substituted carboxylic acid amidesof general formula

the tautomers, the enantiomers, the diastereomers, the mixtures thereofand the salts thereof, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases, which have valuableproperties.

The compounds of the above general formula I as well as the tautomers,the enantiomers, the diastereomers, the mixtures thereof and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases, and their stereoisomers havevaluable pharmacological properties, particularly an antithromboticactivity and a factor Xa-inhibiting activity.

The present application thus relates to the new compounds of the abovegeneral formula I, the preparation thereof, the pharmaceuticalcompositions containing the pharmacologically effective compounds, thepreparation and use thereof.

In the above general formula in a first embodiment

A denotes a group of general formula

whereinm denotes the number 1 or 2,R^(6a) independently of one another denotes a hydrogen, fluorine,chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group andR^(6b) independently of one another may be a hydrogen atom, aC₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkyloxycarbonyl orC₁₋₃-alkylsulphonyl group, with the proviso that

-   -   in the above-mentioned substituted 5- to 7-membered groups A the        heteroatoms optionally introduced as substituents are not        separated from another heteroatom by precisely one carbon atom,        or        a group of general formula

wherein

-   -   m denotes the number 1 or 2,    -   X¹ denotes an oxygen atom or a methylene, —NR^(6b)—, carbonyl or        sulphonyl group,    -   X² denotes an oxygen atom or a —NR^(6b) group,    -   X³ denotes a methylene, carbonyl or sulphonyl group,    -   X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonyl        group,    -   X⁵ denotes a carbonyl or sulphonyl group,    -   X⁶ denotes an oxygen atom, a —NR^(6b) or methylene group,    -   X⁷ denotes an oxygen or sulphur atom or a —NR^(6b) group,    -   X⁸ denotes a methylene or carbonyl group,    -   X⁹ denotes a —NR^(6b) or carbonyl group,    -   X¹⁰ denotes a sulphinyl or sulphonyl group and    -   R^(6a) independently of one another denote a hydrogen, fluorine,        chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,        C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or        C₁₋₃-alkylcarbonylamino group and    -   R^(6b) independently of one another may be a hydrogen atom, a        C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or        C₁₋₃-alkylsulphonyl group, with the proviso that        -   in the above-mentioned substituted 5- to 7-membered groups A            the heteroatoms optionally introduced as substituents are            not separated from another heteroatom by precisely one            carbon atom,            R¹ denotes a hydrogen, fluorine, chlorine or bromine atom, a            C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or            partly replaced by fluorine atoms, a C₂₋₃-alkenyl,            C₂₋₃-alkynyl, nitro, amino, C₁₋₃-alkoxy, a mono-, di- or            trifluoromethoxy group,            R² denotes a hydrogen, fluorine, chlorine or bromine atom or            a C₁₋₃-alkyl group,            R³ denotes a hydrogen atom, a C₂₋₃-alkenyl or C₂₋₃-alkynyl            group or a straight-chain or branched C₁₋₆-alkyl group            wherein the hydrogen atoms may be wholly or partly replaced            by fluorine atoms, and which is optionally substituted by a            nitrile, hydroxy, a C₁₋₆-alkyloxy group wherein the hydrogen            atoms may be wholly or partly replaced by fluorine atoms, an            allyloxy, propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy,            C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,            C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy,            C₁₋₈-alkyloxycarbonylamino, mercapto, C₁₋₃-alkylsulphanyl,            C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,            C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl,            C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl,            C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy,            C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl,            propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl,            C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            C₃₋₆-cycloalkyleneiminocarbonyl, aminosulphonyl,            C₁₋₃-alkylaminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl,            C₃₋₆-cycloalkyleneiminosulphonyl, amino, C₁₋₃-alkylamino,            di-(C₁₋₃-alkyl)-amino, C₁₋₅-alkylcarbonylamino,            C₁₋₃-alkyl-sulphonylamino,            N—(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino,            C₃₋₆-cycloalkylcarbonyl-amino, aminocarbonylamino,            C₁₋₃-alkylaminocarbonylamino,            di-(C₁₋₃-alkyl)-amino-carbonylamino, a 4- to 7-membered            cycloalkyleneiminocarbonylamino, benzyl-oxycarbonylamino,            phenylcarbonylamino or guanidino group,            a carboxy, aminocarbonyl, C₁₋₄-alkylaminocarbonyl,            C₃₋₆-cycloalkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            C₁₋₄-alkoxycarbonyl, C₄₋₆-cycloalkyleneiminocarbonyl group,            a phenyl or heteroaryl, phenylcarbonyl-C₁₋₃-alkyl,            phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is            optionally mono- or polysubstituted in the phenyl or            heteroaryl moiety by fluorine, chlorine or bromine atoms,            C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,            hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy,            benzyloxy, carboxy-C₁₋₃-alkyloxy,            C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy,            aminocarbonyl-C₁₋₃-alkyloxy,            C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy,            di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to            7-membered cycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy,            C₁₋₃-alkyloxycarbonyl or C₁₋₃-alkyloxycarbonylamino group,            a 3- to 7-membered cycloalkyl, cycloalkyleneimino,            cycloalkyl-C₁₋₃-alkyl or cycloalkyleneimino-C₁₋₃-alkyl group            wherein in the cyclic moiety a methylene group may be            replaced by an —NH— group optionally substituted by a            C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group or by an oxygen atom            and wherein additionally a methylene group adjacent to the            —NH—, —N(C₁₋₃-alkylcarbonyl)— or —N(C₁₋₃-alkyl)-group may be            replaced in each case by a carbonyl or sulphonyl group, with            the proviso that a cycloalkyleneimino group as hereinbefore            defined wherein two nitrogen atoms are separated from one            another by precisely one —CH₂— group is excluded,            R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group or            R³ and R⁴ together with the carbon atom to which they are            bound, denote a O₃₋₇-cycloalkyl group, while    -   one of the methylene groups of the C₃₋₇-cycloalkyl group may be        replaced by an imino, C₁₋₃-alkylimino, acylimino or        sulphonylimino group,        R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,        B denotes a group of formula

wherein

-   -   n denotes the number 1 or 2,    -   R⁷ denotes a hydrogen atom or a C₁₋₃-alkyl, hydroxy,        C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group        and    -   R⁸ independently of one another denote a hydrogen, fluorine,        chlorine, bromine or iodine atom, a C₁₋₃-alkyl group wherein the        hydrogen atoms may be wholly or partly replaced by fluorine        atoms, a C₂₋₃-alkenyl or C₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy,        trifluoromethoxy, amino, nitro or nitrile group,        while, unless otherwise stated, by the term “heteroaryl group”        mentioned hereinbefore in the definitions is meant a monocyclic        5- or 6-membered heteroaryl group, while    -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl, phenyl or        phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl, phenyl,        amino-C₂₋₃-alkyl, C₁₋₃-alkylamino-C₂₋₃-alkyl,        di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to 7-membered        cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group or an        oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl or        phenyl-C₁₋₃-alkyl group and two or three nitrogen atoms,        and moreover a phenyl ring optionally substituted by a fluorine,        chlorine or bromine atom, a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy        group, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or        C₃₋₆-cycloalkyleneimino group may be fused to the        above-mentioned monocyclic heteroaryl groups via two adjacent        carbon atoms    -   and the bond is effected via a nitrogen atom or a carbon atom of        the heterocyclic moiety or a fused-on phenyl ring,        while the alkyl and alkoxy groups contained in the        above-mentioned definitions which have more than two carbon        atoms may, unless otherwise stated, be straight-chain or        branched and the alkyl groups in the previously mentioned        dialkylated groups, for example the dialkylamino groups, may be        identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

Examples of monocyclic heteroaryl groups are the pyridyl, N-oxy-pyridyl,pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1,2,3]triazinyl,[1,3,5]triazinyl, [1,2,4]triazinyl, pyrrolyl, imidazolyl,[1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl, furanyl, isoxazolyl,oxazolyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolyl, furazanyl, thiophenyl,thiazolyl, isothiazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolyl or[1,2,5]thiadiazolyl group.

Examples of bicyclic heteroaryl groups are the benzimidazolyl,benzofuranyl, benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl,benzothiazolyl, benzo[c]-isothiazolyl, benzo[d]isothiazolyl,benzoxazolyl, benzo[c]isoxazolyl, benzo[d]-isoxazolyl,benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl,benzo[1,2,3]thia-diazolyl, benzo[d][1,2,3]triazinyl,benzo[1,2,4]triazinyl, benzotriazolyl, cinnolinyl, quinolinyl,N-oxy-quinolinyl, isoquinolinyl, quinazolinyl, N-oxy-quinazolinyl,quinoxalinyl, phthalazinyl, indolyl, isoindolyl or1-oxa-2,3-diaza-indenyl group.

Examples of the C₁₋₈-alkyl groups mentioned hereinbefore in thedefinitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl,sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl,1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl,1-octyl, 2-octyl, 3-octyl or 4-octyl group.

Examples of the C₁₋₈-alkyloxy groups mentioned hereinbefore in thedefinitions are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy,n-butyloxy, sec-butyloxy, tert-butyloxy, 1-pentyloxy, 2-pentyloxy,3-pentyloxy, neo-pentyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy,1-heptyloxy, 2-heptyloxy, 3-heptyloxy, 4-heptyloxy, 1-octyloxy,2-octyloxy, 3-octyloxy or 4-octyloxy group.

By a group which can be converted in vivo into a carboxy group is meantfor example a carboxy group esterified with an alcohol wherein thealcohol moiety is preferably a C₁₋₈-alkanol, a phenyl-C₁₋₃-alkanol, aC₃₋₉-cycloalkanol, a C₅₋₇-cycloalkenol, a C₃₋₅-alkenol, aphenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol or phenyl-C₃₋₅-alkynol with theproviso that no bond to the oxygen atom starts from a carbon atom whichcarries a double or triple bond, a C₃₋₈-cycloalkyl-C₁₋₃-alkanol or analcohol of formula

R⁹—CO—O—(R¹⁰CR¹¹)—OH,

wherein

-   -   R⁹ denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or        phenyl-C₁₋₃-alkyl group,    -   R¹⁰ denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or        phenyl group and        R¹¹ denotes a hydrogen atom or a C₁₋₃-alkyl group.

Preferred groups which may be cleaved from a carboxy group in vivoinclude a C₁₋₆-alkoxy group such as the methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyl-oxy, n-pentyloxy, n-hexyloxy or cyclohexyloxygroup or a phenyl-C₁₋₃-alkoxy group such as the benzyloxy group.

Those compounds of general formula I wherein R³ contains a group whichmay be converted in vivo into a carboxy group are prodrugs for thosecompounds of general formula I wherein R³ contains a carboxy group.

A 2nd embodiment of the present invention comprises those compounds ofgeneral formula I wherein

A denotes a group of general formula

wherein m denotes the number 1 or 2,R^(6a) independently of one another denote a hydrogen or fluorine atom,a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group andR^(6b) independently of one another may be a hydrogen atom, aC₁₋₄-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxycarbonyl orC₁₋₃-alkylsulphonyl group, with the proviso that

-   -   in the above-mentioned substituted 5- to 7-membered groups A the        heteroatoms optionally introduced as substituents are not        separated from another heteroatom by precisely one carbon atom,        or        a group of general formula

wherein

-   -   m denotes the number 1 or 2,    -   X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group,    -   X² denotes an oxygen atom or a —NR^(6b) group,    -   X³ denotes a methylene, carbonyl or sulphonyl group,    -   X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonyl        group,    -   X⁵ denotes a carbonyl or sulphonyl group,    -   X⁸ denotes a carbonyl group,    -   X⁹ denotes a carbonyl group,    -   R^(6a) independently of one another denote a hydrogen or        fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group        and    -   R^(6b) independently of one another may be a hydrogen atom, a        C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or        C₁₋₃-alkylsulphonyl group, with the proviso that        -   in the above-mentioned substituted 5- to 7-membered cyclic            groups A the heteroatoms introduced as substituents are not            separated from another heteroatom by precisely one carbon            atom,            R¹ denotes a hydrogen, fluorine, chlorine or bromine atom, a            C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or            partly replaced by fluorine atoms, a C₂₋₃-alkenyl,            C₂₋₃-alkynyl, nitro, amino, C₁₋₃-alkoxy, a mono-, di- or            trifluoromethoxy group,            R² denotes a hydrogen, fluorine, chlorine or bromine atom or            a C₁₋₃-alkyl group,            R³ denotes a C₂₋₃-alkenyl or C₂₋₃-alkynyl group or a            straight-chain or branched C₁₋₈-alkyl group wherein the            hydrogen atoms may be wholly or partly replaced by fluorine            atoms, and which is optionally substituted by a nitrile,            hydroxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms            may be wholly or partly replaced by fluorine atoms, an            allyloxy, propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy,            C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,            C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy,            C₁₋₈-alkyloxycarbonylamino, mercapto, C₁₋₃-alkylsulphanyl,            C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,            C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl,            C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl,            C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy,            C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl,            propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl,            C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            C₃₋₆-cycloalkyleneiminocarbonyl, aminosulphonyl,            C₁₋₃-alkylaminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl,            C₃₋₆-cycloalkyleneiminosulphonyl, amino, C₁₋₃-alkyl-amino,            di-(C₁₋₃-alkyl)-amino, C₁₋₅-alkylcarbonylamino,            C₁₋₃-alkylsulphonylamino,            N—(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino,            C₃₋₆-cycloalkylcarbonylamino, aminocarbonylamino,            C₁₋₃-alkylaminocarbonylamino,            di-(C₁₋₃-alkyl)-aminocarbonylamino, a 4- to 7-membered            cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino,            phenylcarbonylamino or guanidino group,            a carboxy, aminocarbonyl, C₁₋₄-alkylaminocarbonyl,            C₃₋₆-cycloalkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            C₁₋₄-alkoxycarbonyl, C₄₋₆-cycloalkyleneiminocarbonyl group,            a phenyl or heteroaryl, phenylcarbonyl-C₁₋₃-alkyl,            phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is            optionally mono- or polysubstituted in the phenyl or            heteroaryl moiety by fluorine, chlorine or bromine atoms,            C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,            hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy,            benzyloxy, carboxy-C₁₋₃-alkyloxy,            C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy,            aminocarbonyl-C₁₋₃-alkyloxy,            C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy,            di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to            7-membered cycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy,            C₁₋₃-alkyloxycarbonyl or C₁₋₃-alkyloxycarbonylamino group,            a 3- to 7-membered cycloalkyl, cycloalkyleneimino,            cycloalkyl-C₁₋₃-alkyl or cycloalkyleneimino-C₁₋₃-alkyl group            wherein in the cyclic moiety a methylene group may be            replaced by a —NH— group optionally substituted by a            C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group or by an oxygen atom            and wherein additionally a methylene group adjacent to the            —NH—, —N(C₁₋₃-alkylcarbonyl)- or —N(C₁₋₃-alkyl)-group may be            replaced in each case by a carbonyl or sulphonyl group, with            the proviso that a cycloalkyleneimino group as hereinbefore            defined wherein two nitrogen atoms are separated from one            another by precisely one —CH₂— group is excluded,            R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group,            R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,            B denotes a group of formula

wherein

-   -   n denotes the number 1 or 2,    -   R⁷ denotes a hydrogen atom, a C₁₋₃-alkyl, hydroxy,        C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group        and    -   R⁸ independently of one another denote a hydrogen, fluorine,        chlorine, bromine or iodine atom, a C₁₋₃-alkyl group wherein the        hydrogen atoms may be wholly or partly replaced by fluorine        atoms, a C₂₋₃-alkenyl or C₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy,        trifluoromethoxy, amino, nitro or nitrile group,        while, unless otherwise stated, by the term “heteroaryl group”        mentioned hereinbefore in the definitions is meant a monocyclic        5- or 6-membered heteroaryl group, while    -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl, phenyl or        phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl, phenyl,        amino-C₂₋₃-alkyl, C₁₋₃-alkylamino-C₂₋₃-alkyl,        di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to 7-membered        cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group or an        oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl or        phenyl-C₁₋₃-alkyl group and two or three nitrogen atoms,    -   and moreover a phenyl ring optionally substituted by a fluorine,        chlorine or bromine atom, a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy        group, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or        C₃₋₆-cycloalkyleneimino group may be fused to the        above-mentioned monocyclic heteroaryl groups via two adjacent        carbon atoms    -   and the bond is effected via a nitrogen atom or a carbon atom of        the heterocyclic moiety or a fused-on phenyl ring,        while the alkyl and alkoxy groups contained in the        above-mentioned definitions which have more than two carbon        atoms may, unless otherwise stated, be straight-chain or        branched and the alkyl groups in the previously mentioned        dialkylated groups, for example the dialkylamino groups, may be        identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

A 3rd embodiment of the present invention comprises those compounds ofgeneral formula I, wherein

A denotes a group of general formula

wherein m denotes the number 1 or 2,R^(6a) independently of one another denote a hydrogen or fluorine atom,a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group andR^(6b) independently of one another may be a hydrogen atom, aC₁₋₄-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxycarbonyl orC₁₋₃-alkylsulphonyl group, with the proviso that

-   -   in the above-mentioned substituted 5- to 7-membered groups A the        heteroatoms optionally introduced as substituents are not        separated from another heteroatom by precisely one carbon atom,        or        a group of general formula

wherein

-   -   m denotes the number 1 or 2,    -   X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group,    -   X² denotes an oxygen atom or a —NR^(6b) group,    -   X³ denotes a methylene, carbonyl or sulphonyl group,    -   X⁴ denotes an oxygen or sulphur atom or a —NR^(6b) group,    -   X⁵ denotes a carbonyl or sulphonyl group,    -   R^(6a) independently of one another denote a hydrogen or        fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group        and    -   R^(6b) independently of one another may be a hydrogen atom, a        C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or        C₁₋₃-alkylsulphonyl group, with the proviso that        -   in the above-mentioned substituted 5- to 7-membered cyclic            groups A the heteroatoms introduced as substituents are not            separated from another heteroatom by precisely one carbon            atom,            R¹ denotes a fluorine, chlorine or bromine atom, a            C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or            partly replaced by fluorine atoms, a nitro, C₁₋₃-alkoxy, a            mono-, di- or trifluoromethoxy group,            R² denotes a hydrogen atom,            R³ denotes a straight-chain or branched C₁₋₆-alkyl group            wherein the hydrogen atoms may be wholly or partly replaced            by fluorine atoms, and which is optionally substituted by a            nitrile, hydroxy, benzyloxy, a C₁₋₅-alkyloxy group wherein            the hydrogen atoms may be wholly or partly replaced by            fluorine atoms, an allyloxy, C₁₋₅-alkylcarbonyloxy,            C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,            C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy,            C₁₋₈-alkyloxycarbonylamino, C₁₋₃-alkylsulphanyl,            C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl,            C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            C₃₋₆-cycloalkyleneiminocarbonyl, aminocarbonylamino,            C₁₋₃-alkylaminocarbonylamino or            di-(C₁₋₃-alkyl)-aminocarbonylamino group, an aminocarbonyl,            C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl or            di-(C₁₋₃-alkyl)-aminocarbonyl group,            a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or            heteroaryl-C₁₋₃-alkyl group which is optionally mono- or            polysubstituted in the phenyl or heteroaryl moiety by            fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, amino,            C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy,            C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or            C₁₋₃-alkyloxycarbonyl group,            a 3- to 7-membered cycloalkyl group wherein in the cyclic            moiety a methylene group may be replaced by a —NH— group            optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl            group, or an oxygen atom,            R⁴ denotes a hydrogen atom,            R⁵ denotes a hydrogen atom,            B denotes a group of formula

wherein

-   -   n denotes the number 1,    -   R⁷ denotes a hydrogen atom and    -   R⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine        atom, a methyl, C₂₋₃-alkynyl, or methoxy group, wherein the        hydrogen atoms may be wholly or partly replaced by fluorine        atoms,        while, unless otherwise stated, by the term “heteroaryl group”        mentioned hereinbefore in the definitions is meant a monocyclic        5- or 6-membered heteroaryl group, while    -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl group, an oxygen or        sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group or        an oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group and        two or three nitrogen atoms,    -   and the bond is effected via a nitrogen atom or via a carbon        atom,        while the alkyl and alkoxy groups contained in the        above-mentioned definitions which have more than two carbon        atoms may, unless otherwise stated, be straight-chain or        branched and the alkyl groups in the previously mentioned        dialkylated groups, for example the dialkylamino groups, may be        identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.        A 4th embodiment of the present invention comprises those        compounds of general formula I wherein        A, R¹, R², R⁴, R⁵ and B are defined as described under the 3rd        embodiment and        R³ denotes a straight-chain or branched C₁₋₆-alkyl group wherein        the hydrogen atoms may be wholly or partly replaced by fluorine        atoms, and which is optionally substituted by a nitrile,        hydroxy, benzyloxy, a C₁₋₅-alkyloxy group wherein the hydrogen        atoms may be wholly or partly replaced by fluorine atoms, an        allyloxy, C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy,        carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyl-oxycarbonyl-C₁₋₃-alkyloxy,        C₁₋₈-alkyloxycarbonylamino, C₁₋₃-alkylsulphanyl,        C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl,        C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        C₃₋₆-cycloalkyleneiminocarbonyl, aminocarbonylamino,        C₁₋₃-alkylaminocarbonylamino or        di-(C₁₋₃-alkyl)-aminocarbonylamino group, an aminocarbonyl,        C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl or        di-(C₁₋₃-alkyl)-aminocarbonyl group,        while the alkyl and alkoxy groups contained in the        above-mentioned definitions which have more than two carbon        atoms may, unless otherwise stated, be straight-chain or        branched and the alkyl groups in the previously mentioned        dialkylated groups, for example the dialkylamino groups, may be        identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

A 5th embodiment of the present invention comprises those compounds ofgeneral formula I wherein

A, R¹, R², R⁴, R⁵ and B are defined as described under the 3rdembodiment andR³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl orheteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstitutedin the phenyl or heteroaryl moiety by fluorine, chlorine or bromineatoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, orC₁₋₃-alkyloxycarbonyl group,a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety amethylene group may be replaced by a —NH— group optionally substitutedby a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or by an oxygen atom,while, unless otherwise stated, by the term “heteroaryl group” mentionedhereinbefore in the definitions is meant a monocyclic 5- or 6-memberedheteroaryl group, while

-   -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl group, an oxygen or        sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group or        an oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group and        two or three nitrogen atoms,    -   and the bond is effected via a nitrogen atom or via a carbon        atom,        while the alkyl groups contained in the foregoing definitions        which have more than two carbon atoms may, unless otherwise        stated, be straight-chain or branched and the alkyl groups in        the previously mentioned dialkylated groups, for example the        dialkylamino groups, may be identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

A 6th embodiment of the present invention comprises those compounds ofgeneral formula I, wherein

A denotes a group of general formula

wherein m denotes the number 1 or 2,R^(6a) independently of one another denote a hydrogen or fluorine atomor a C₁₋₃-alkyl group andR^(6b) may be a hydrogen atom or a C₁₋₃-alkyl group, with the provisothat

-   -   in the above-mentioned substituted 5- to 7-membered groups A the        heteroatoms optionally introduced as substituents are not        separated from another heteroatom by precisely one carbon atom,        or        a group of general formula

wherein

-   -   m denotes the number 1 or 2,    -   X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group,    -   X² denotes an oxygen atom or a —NR^(6b) group,    -   X³ denotes a methylene, carbonyl or sulphonyl group,    -   X⁴ an oxygen or sulphur atom or a —NR^(6b) group,    -   X⁵ denotes a carbonyl or sulphonyl group,    -   R^(6a) independently of one another denote a hydrogen or        fluorine atom or a C₁₋₃-alkyl group and    -   R^(6b) independently of one another may be a hydrogen atom or a        C₁₋₃-alkyl group, with the proviso that        -   in the above-mentioned substituted 5- to 7-membered cyclic            groups A the heteroatoms introduced as substituents are not            separated from another heteroatom by precisely one carbon            atom,            R¹ denotes a chlorine or bromine atom, a methyl or methoxy            group, wherein the hydrogen atoms may be wholly or partly            replaced by fluorine atoms, or a nitro group,            R² denotes a hydrogen atom,            R³ denotes a straight-chain or branched C₁₋₄-alkyl group            wherein the hydrogen atoms may be wholly or partly replaced            by fluorine atoms, and which is optionally substituted by a            hydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms            may be wholly or partly replaced by fluorine atoms, a            C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy or            C₁₋₃-alkyloxycarbonyl group,            a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or            heteroaryl-C₁₋₃-alkyl group which is optionally mono- or            polysubstituted in the phenyl or heteroaryl moiety by            fluorine, chlorine or bromine atoms, C₁₋₃-alkyl,            C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or            C₁₋₃-alkyloxycarbonyl group,            R⁴ denotes a hydrogen atom,            R⁵ denotes a hydrogen atom and            B denotes a group of formula

whereinn denotes the number 1,R⁷ denotes a hydrogen atom andR⁸ denotes a chlorine or bromine atom or the ethynyl group,while, unless otherwise stated, by the term “heteroaryl group” mentionedhereinbefore in the definitions is meant a monocyclic 5- or 6-memberedheteroaryl group, while

-   -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl group, an oxygen or        sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group or        an oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group and        two or three nitrogen atoms,    -   and the bond is effected via a nitrogen atom or via a carbon        atom,        while the alkyl groups contained in the foregoing definitions        which have more than two carbon atoms may, unless otherwise        stated, be straight-chain or branched and the alkyl groups in        the previously mentioned dialkylated groups, for example the        dialkylamino groups, may be identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.        A 7th embodiment of the present invention comprises those        compounds of general formula I, wherein        A, R¹, R², R⁴, R⁵ and B are defined as described under the 6th        embodiment and        R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein        the hydrogen atoms may be wholly or partly replaced by fluorine        atoms, and which is optionally substituted by a hydroxy, a        C₁₋₄-alkyloxy group wherein the hydrogen atoms may be wholly or        partly replaced by fluorine atoms, a C₁₋₃-alkylsulphanyl,        C₁₋₃-alkylsulphonyl, carboxy or C₁₋₃-alkyloxycarbonyl group,        while the alkyl and alkoxy groups contained in the        above-mentioned definitions which have more than two carbon        atoms may, unless otherwise stated, be straight-chain or        branched and the alkyl groups in the previously mentioned        dialkylated groups, for example the dialkylamino groups, may be        identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

An 8th embodiment of the present invention comprises those compounds ofgeneral formula I, wherein

A, R¹, R², R⁴, R⁵ and B are defined as described under the 6thembodiment andR³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl orheteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstitutedin the phenyl or heteroaryl moiety by fluorine, chlorine or bromineatoms, C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy,carboxy, or C₁₋₃-alkyloxycarbonyl group,a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety amethylene group may be replaced by a —NH— group optionally substitutedby a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or by an oxygen atom,while, unless otherwise stated, by the term “heteroaryl group” mentionedhereinbefore in the definitions is meant a monocyclic 5- or 6-memberedheteroaryl group, while

-   -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl group, an oxygen or        sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group or        an oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group and        two or three nitrogen atoms,    -   and the bond is effected via a nitrogen atom or via a carbon        atom,        while the alkyl groups contained in the foregoing definitions        which have more than two carbon atoms may, unless otherwise        stated, be straight-chain or branched and the alkyl groups in        the previously mentioned dialkylated groups, for example the        dialkylamino groups, may be identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms, the tautomers, the enantiomers, the        diastereomers, the mixtures thereof and the salts thereof.

A 9th embodiment of the present invention comprises those compounds ofgeneral formula I, wherein

A denotes a group of formula

wherein

-   -   m denotes the number 1 or 2,    -   R^(6a) independently of one another denote a hydrogen or        fluorine atom or a C₁₋₃-alkyl group, with the proviso that        -   in the above-mentioned substituted 5- to 7-membered cyclic            groups A the fluorine atoms introduced as substituents are            not separated from another heteroatom by precisely one            carbon atom,            R¹ denotes a chlorine or bromine atom, a methyl or methoxy            group, wherein the hydrogen atoms may be wholly or partly            replaced by fluorine atoms, or a nitro group,            R² denotes a hydrogen atom,            R³ denotes a straight-chain or branched C₁₋₄-alkyl group            wherein the hydrogen atoms may be wholly or partly replaced            by fluorine atoms, and which is optionally substituted by a            hydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms            may be wholly or partly replaced by fluorine atoms, a            C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy or            C₁₋₃-alkyloxycarbonyl group,            a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl,            oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl,            pyrazinyl, pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl            group which may optionally be substituted in the heteroaryl            moiety by one or two C₁₋₃-alkyl groups, C₁₋₃-alkyloxy            groups, carboxy or C₁₋₃-alkyloxycarbonyl groups, and            R⁴ denotes a hydrogen atom,            R⁵ denotes a hydrogen atom and            B denotes a group of formula

whereinn denotes the number 1,R⁷ denotes a hydrogen atom andR⁸ denotes a chlorine or bromine atom or an ethynyl group,while, unless otherwise stated, by the term “heteroaryl group” mentionedhereinbefore in the definitions is meant a monocyclic 5- or 6-memberedheteroaryl group, while

-   -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl group, an oxygen or        sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group or        an oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group and        two or three nitrogen atoms,    -   and the bond is effected via a nitrogen atom or via a carbon        atom,        while the alkyl groups contained in the foregoing definitions        which have more than two carbon atoms may, unless otherwise        stated, be straight-chain or branched and the alkyl groups in        the previously mentioned dialkylated groups, for example the        dialkylamino groups, may be identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

A 10th embodiment of the present invention comprises those compounds ofgeneral formula I, wherein

A, R¹, R², R⁴, R⁵ and B are defined as described under the 9thembodiment andR³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, andwhich is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy groupwherein the hydrogen atoms may be wholly or partly replaced by fluorineatoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy orC₁₋₃-alkyloxycarbonyl group,while the alkyl and alkoxy groups contained in the above-mentioneddefinitions which have more than two carbon atoms may, unless otherwisestated, be straight-chain or branched and the alkyl groups in thepreviously mentioned dialkylated groups, for example the dialkylaminogroups, may be identical or different,and the hydrogen atoms of the methyl or ethyl groups contained in theforegoing definitions may be wholly or partly replaced by fluorineatoms,the tautomers, the enantiomers, the diastereomers, the mixtures thereofand the salts thereof.

An 11th embodiment of the present invention comprises those compounds ofgeneral formula I wherein

A, R¹, R², R⁴, R⁵ and B are defined as described under the 9thembodiment and denote a furanyl, thiophenyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl group which mayoptionally be substituted in the heteroaryl moiety by one or twoC₁₋₃-alkyl groups, wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, C₁₋₃-alkyloxy groups, wherein the hydrogenatoms may be wholly or partly replaced by fluorine atoms, carboxy orC₁₋₃-alkyloxycarbonyl groups, andunless otherwise stated, by the term “heteroaryl group” mentionedhereinbefore in the definitions is meant a monocyclic 5- or 6-memberedheteroaryl group, while

-   -   the 6-membered heteroaryl group contains one, two or three        nitrogen atoms and    -   the 5-membered heteroaryl group contains an imino group        optionally substituted by a C₁₋₃-alkyl group, an oxygen or        sulphur atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group or        an oxygen or sulphur atom and additionally a nitrogen atom or    -   an imino group optionally substituted by a C₁₋₃-alkyl group and        two or three nitrogen atoms,    -   and the bond is effected via a nitrogen atom or via a carbon        atom,        while the alkyl groups contained in the foregoing definitions        which have more than two carbon atoms may, unless otherwise        stated, be straight-chain or branched and the alkyl groups in        the previously mentioned dialkylated groups, for example the        dialkylamino groups, may be identical or different,        and the hydrogen atoms of the methyl or ethyl groups contained        in the foregoing definitions may be wholly or partly replaced by        fluorine atoms,        the tautomers, the enantiomers, the diastereomers, the mixtures        thereof and the salts thereof.

A 12th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7and 8, wherein the group X¹ denotes a methylene group.

A 13th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7and 8, wherein the group X¹ denotes a carbonyl group.

A 14th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 12 and 13, wherein the group X³ denotes a methylene group.

A 15th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 12 and 13 wherein the group X³ denotes a carbonyl group.

A 16th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 12, 13, 14 and 15, wherein the group X⁴ denotes an oxygen atom.

A 17th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the group B denotes thegroup

An 18th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the group B denotes thegroup

A 19th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the group B denotes thegroup

A 20th embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein the group R⁸denotes a chlorine atom.

A 21st embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein the group R⁸denotes a bromine atom.

A 22nd embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein the group R⁸denotes an ethynyl group.

A 23rd embodiment of the present invention comprises those compounds ofgeneral formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22, whichcorrespond to general formula Ia

The following preferred compounds of general formula I will now bementioned by way of example:

-   (1)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-benzamide,-   (2)    4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide,-   (3)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide,-   (4)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide,-   (5)    4-(4-N-acetyl-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide,-   (6)    4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide,-   (7)    4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-benzamide,-   (8)    4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide,-   (9)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1-yl)-benzamide,-   (10)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide,-   (11)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide,-   (12)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide,-   (13)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(2-methyl-pyrrolidin-1-yl)-benzamide,-   (14)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-chloro-4-(morpholin-1-yl)-benzamide,-   (15)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3,5-difluoro-4-(morpholin-1-yl)-benzamide,-   (16)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-4-(morpholin-1-yl)-benzamide,-   (17)    4-(azepan-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide,-   (18)    4-(azepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide,-   (19)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-1-yl)-benzamide,-   (20)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]oxazepan-4-yl)-benzamide,-   (21)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide,-   (22)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (23)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (24)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (25)    4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide,-   (26)    4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide,-   (27)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (28)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (29)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (30)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide,-   (31)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide,-   (32)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (33)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(N-methyl-piperazin-1-yl)-3-trifluoromethyl-benzamide,-   (34)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (35)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(pyrrolidin-2-on-1-yl)-benzamide,-   (36)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-4-(pyrrolidin-2-on-1-yl)-benzamide,-   (37)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-1-yl)-benzamide,-   (38)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,4-didehydro-piperidin-1-yl)-benzamide,-   (39)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide-   (40)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide,-   (41)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide,-   (42)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide,-   (43)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,-   (44)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (45)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide,-   (46)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide,-   (47)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (48)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzamide,-   (49)    N-[1-(5-chloro-1H-indol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (50)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-[2-(4-methyl-piperazin-1-yl-methyl)-piperidin-1-yl)-benzamide,-   (51)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(oxazolidin-2-on-3-yl)-benzamide,-   (52)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (53)    N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (54)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-1-yl)-benzamide,-   (55)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide,-   (56)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (57)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide,-   (58)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide,-   (59)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethyl-benzamide,-   (60)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide,-   (61)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-didehydro-azepan-2-on-1-yl)-benzamide,-   (62)    4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-6-fluoro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide,-   (63)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,3-dioxo-thiomorpholin-4-yl)-3-methyl-benzamide,-   (64)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(1,1,3-trioxo-thiomorpholin-4-yl)-benzamide,-   (65)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide,-   (66)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide,-   (67)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (68)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide,-   (69)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide,-   (70)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide,-   (71)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,-   (72)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,-   (73)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,-   (74)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,-   (75)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (76)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (77)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (78)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (79)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (80)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide,-   (81)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (82)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide,-   (83)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide,-   (84)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide,-   (85)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethoxy-benzamide,-   (86)    3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-benzamide,-   (87)    3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide,-   (88)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(furan-2-yl)-methyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (89)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,2]oxazinan-2-yl)-benzamide,-   (90)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide,-   (91)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide,-   (92)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide,-   (93)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (94)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (95)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (96)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (97)    3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (98)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(7-oxo-[1,4]diazepan-1-yl)-benzamide,-   (99)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (100)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide,-   (101)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,-   (102)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (103)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (104)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4R)-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (105)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-(4R)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (106)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide,-   (107)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (108)    N-[1-(1S)-(5-chloro-1H-benzimidazol-2-yl)-2-cyano-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (109)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-pyridin-3-yl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (110)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (111)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide,-   (112)    3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylamino-pyrrolidin-1-yl)-benzamide,-   (113)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzamide,-   (114)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide,-   (115)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-([1,4]diazepan-1-yl)-benzamide,-   (116)    3-chloro-N-[1-(5-chloro-1H-indol-2-yl)-2-methoxy-ethyl]-4-([1,4]diazepan-1-yl)-benzamide,-   (117)    N-[1-(5-chloro-1H-indol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (118)    3-bromo-N-[1-(5-chloro-1H-indol-2-yl)-1-(furan-2-yl)-methyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (119)    N-[1-(5-bromo-1H-indol-2-yl)-1-(1-methyl-1H-pyrazol-3-yl)-methyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,-   (120)    N-[1-(5-chloro-1H-indol-2-yl)-3-(methyl-sulphonyl)-propyl]-3-methyl-4-(tetrahydropyrimidin-2-on-1-yl)-benzamide,-   (121)    N-[1-(5-chloro-1H-indol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(5-methyl-pyrrolidin-2-on-1-yl)-benzamide,-   (122)    N-[1-(5-chloro-1H-indol-2-yl)-1-phenyl-methyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide,-   (123)    4-(azepan-2-on-1-yl)-3-chloro-N-[1-(5-chloro-1H-indol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-benzamide,-   (124)    N-[1-(5-bromo-1H-indol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide,-   (125)    3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-4-(diazepan-1-yl)-benzamide,-   (126)    3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (127)    N-[(1S)-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (128)    N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (129)    3-bromo-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (130)    N-[1-(7-bromo-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-chloro-4-(4-methyl-piperazin-1-yl)-benzamide,-   (131)    N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (132)    N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(furan-2-yl)-methyl]-4-(diazepan-1-yl)-3-trifluoromethyl-benzamide,-   (133)    N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-phenyl-methyl]-3-methyl-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-benzamide,-   (134)    3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (135)    3-bromo-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-(methyl-sulphanyl)-propyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide,-   (136)    3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-4-(piperazin-2-on-1-yl)-benzamide,-   (137)    N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (138)    N-[1-(7-bromo-imidazo[1,2a]pyridin-2-yl)-3-methoxy-propyl]-3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide,-   (139)    N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-trifluoromethoxy-ethyl]-3-methyl-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (140)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (141)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-benzyloxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (142)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-benzyloxycarbonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (143)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (144)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyrazin-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (145)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(oxazol-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (146)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-imidazol-4-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (147)    N[1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-difluoromethoxy-4-(morpholin-3-on-4-yl)-benzamide,-   (148)    N[1-(5-chloro-1H-benzimidazol-2-yl)-1-methyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (149)    N-[3-(5-chloro-1H-benzimidazol-2-yl)-tetrahydrofuran-3-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (150)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-(pyrrolidin-1-yl-carbonyl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (151)    N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (152)    N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (153)    N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (154)    3-bromo-N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (155)    N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-methyl-oxazolidin-2-on-3-yl)-benzamide,-   (156)    N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (157)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(2-methyl-tetrahydropyridazin-1-yl)-benzamide,    the tautomers, the enantiomers, the diastereomers, the mixtures    thereof and the salts thereof, while the compounds-   (1)    4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-benzamide,-   (2)    4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide,-   (3)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide,-   (4)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide,-   (5)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (6)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (7)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (8)    4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide,-   (9)    4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide,-   (10)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,-   (11)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide,-   (12)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,-   (13)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,-   (14)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide,-   (15)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (16)    N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (17)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide,-   (18)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (19)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide,-   (20)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethyl-benzamide,-   (21)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide,-   (22)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (23)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide,-   (24)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,-   (25)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (26)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (27)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (28)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (29)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide,-   (30)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (31)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide,-   (32)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide,-   (33)    3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-benzamide,-   (34)    3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide,-   (35)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(furan-2-yl)-methyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,-   (36)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide,-   (37)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (38)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (39)    3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,-   (40)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (41)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide,-   (42)    N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,-   (43)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (44)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (45)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4R)-methyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (46)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-(4R)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide,-   (47)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide,-   (48)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (49)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (50)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide,-   (51)    3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide,-   (52)    N-[1-(5-chloro-1H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,-   (53)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide-   (54)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide,-   (55)    N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide,-   (56)    N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide,-   (57)    N-[(1S)-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,    the tautomers, the enantiomers, the diastereomers, the mixtures    thereof and the salts thereof are particularly preferred.

Within the scope of the present application, where applicable, the“isomer”, “stereoisomer”, “diastereomer”, “enantiomer”, “chiral”,“racemate” or “racemic mixture” are defined as follows. Compounds of thesame empirical formula which differ in the nature or arrangement of thebonding of their atoms or their connectivity or the spatial arrangementof the atoms in the molecule are known as “isomers”. Isomers whichdiffer in the spatial arrangement of the atoms in the molecule and arenot congruent, while having the same type of connectivity of theiratoms, are known as “stereoisomers”. Stereoisomers which do not behaveas image and mirror image to one another are known as “diastereomers”,and stereoisomers which behave as an image and mirror image to oneanother are known as “enantiomers”. Where an asymmetric centre or atomis present (also known as a stereocentre or chiral centre), for examplein the case of a carbon atom substituted by four different substituents,the molecule has the attribute “chiral”, and a pair of enantiomers ispossible. An enantiomer may be characterised by the absoluteconfiguration of its stereocentre. The absolute configuration isdescribed by means of the descriptors (R) and (S), which are determinedby the application of the sequence rules according to Cahn, Ingold andPrelog, or by describing the rotation of the plane of polarised light asit interacts with the molecule, which is referred to as dextrorotatoryor laevorotatory (i.e. accordingly with (+) or (−) as the descriptor). Achiral compound may occur both as an individual enantiomer or as amixture of the corresponding enantiomers. A mixture which contains equalamounts of both enantiomers of a compound is known as a “racemate” or“racemic mixture”.

According to the invention the compounds of general formula I areobtained by methods known per se, for example by the following methods:

(a) In order to prepare compounds of general formula

wherein R³ to R⁵ are as hereinbefore defined and Z¹ denotes the hydrogenatom or a protective group and B′ denotes a group of formula

wherein R⁷ and R⁸ are as hereinbefore defined:cyclisation of a compound of general formula

optionally formed in the reaction mixturewhereinR³ to R⁵, R⁷ and R⁸ are as hereinbefore defined and Z¹ denotes thehydrogen atom or a protective group, after which any protective groupused is cleaved.

The cyclisation is conveniently carried out in a solvent or mixture ofsolvents such as ethanol, isopropanol, glacial acetic acid, benzene,chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,diethyleneglycoldimethylether, sulpholane, dimethylformamide ortetralin, dimethylsulphoxide, methylene chloride, chloroform,tetrachloromethane, for example at temperatures between 0 and 250° C.,but preferably between 20 and 100° C., optionally in the presence of acondensation agent such as phosphorus oxychloride, thionyl chloride,sulphurylchloride, sulphuric acid, p-toluenesulphonic acid,methanesulphonic acid, hydrochloric acid, phosphoric acid,polyphosphoric acid, acetic acid, acetic anhydride, N,N′dicyclohexylcarbodiimide or optionally also in the presence of a basesuch as potassium ethoxide or potassium-tert.-butoxide. The cyclisationmay however also be carried out without a solvent and/or condensationagent.

Compounds of general formula (IV) may be obtained by acylation ofcompounds of general formula

wherein n, R⁷ and R⁸ are as hereinbefore defined, with compounds ofgeneral formula

wherein R³, R⁴ and R⁵ are as hereinbefore defined, Q denotes a halogenatom or a hydroxy, C₁₋₄-alkoxy or C₁₋₄-acyloxy group and Z¹ denotes aprotective group, according to processes described in (e).(b) In order to prepare a compound of general formula

wherein R³ to R⁵ are as hereinbefore defined, Z¹ denotes the hydrogenatom or a protective group, for example a C₁₋₅-alkyloxycarbonyl orbenzyloxycarbonyl group, and B′ denotes a group of formula

wherein R′ and R⁸ are as hereinbefore defined:

-   -   i) transition metal-catalysed coupling and cyclisation of a        compound of general formula

-   -   wherein R³ denotes a phenyl or heteroaryl group and R⁴ denotes a        hydrogen atom and R⁵ is as hereinbefore defined, with a compound        of general formula

-   -   wherein R⁸ is as hereinbefore defined and Z¹ denotes a        protective group, for example an acetyl or methylsulphonyl        group, after which the protective group is cleaved.

The reaction sequence is conveniently carried out in a solvent ormixture of solvents such as ethanol, isopropanol, glacial acetic acid,benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,diethyleneglycoldimethylether, sulpholane, dimethylformamide,N-methylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride,chloroform or tetrachloromethane, for example at temperatures between 0and 250° C., but preferably between 20 and 120° C., conveniently in thepresence of transition metal catalysts such asbis-(triphenylphosphine)-palladium(II)-chloride,bis-(tricyclohexylphosphine)-palladium(II)-chloride,bis-(triethylphosphine)-palladium(II)-chloride orbis-(tri-o-tolylphosphine)-palladium(II)-chloride and optionally in thepresence of a transition metal catalyst such as copper(I)-iodide,copper(I)-bromide or copper(I)-acetate and conveniently in the presenceof a base

-   -   such as tetramethylguanidine, tetramethylethylenediamine or N,N′        dimethylethylenediamine as well as optionally using an inert gas        atmosphere (for example nitrogen or argon).    -   ii) alkylation and subsequent reductive amination of a compound        of general formula

-   -   wherein R⁷ and R⁸ are as hereinbefore defined and Y denotes a        halogen atom, a C₁₋₄-alkoxy, C₁₋₄-alkoxyamino or a        N—C₁₋₄-alkoxy-N—C₁₋₄-alkyl-amino group, with a compound of        general formula

R⁴-M,  (IX)

-   -   wherein R⁴ is as hereinbefore defined and M denotes a metal such        as for example lithium, sodium or potassium, or a metal such as        for example magnesium, cadmium, copper or zinc, with a suitable        counter-ion, such as for example chloride, bromide or iodide, or        also a combination of two metals, such as for example magnesium        and copper, lithium and copper or zinc and copper, with suitable        counter-ions, such as for example cyanide, chloride, bromide or        iodide, as well as a grouping containing combinations thereof,        and subsequent reductive amination of the compounds thus        obtained.

The alkylation is conveniently carried out in a solvent or mixture ofsolvents such as benzene, chlorobenzene, toluene, xylene,glycoldimethylether, diethyleneglycoldimethylether, sulpholane,dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide,methylene chloride, chloroform, tetrachloromethane, diethyl ether,tert.-butyl-methyl-ether or tetrahydrofuran, for example, attemperatures between −100 and +100° C., but preferably between −100 and30° C., with alkylating reagents such as Grignard reagents,organolithium reagents, Gilman or Knochel cuprates which may be producedby methods known from the literature, optionally using an inert gasatmosphere (nitrogen or argon). The subsequent reductive amination ofthe ketones formed after alkylation is carried out for example byreaction with ammonia, hydroxylamine, alkoxylamines, primary amines,hydroxyl-alkylamines or alkoxy-alkylamines followed by or accompanied byreduction, for example with hydride donors such as sodium borohydride,lithium aluminium hydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride or diisobutylaluminium hydride in a solvent ormixture of solvents such as ethanol, isopropanol, benzene, toluene,pyridine, ethyleneglycol-dimethylether, diethyleneglycoldimethylether,N-alkylmorpholine, diethyl ether, tert.-butyl-methylether,tetrahydrofuran, hexane or cyclohexane or by hydrogenation optionallyunder pressure and conveniently in the presence of a catalyst such asRaney nickel, palladium, palladium charcoal, platinum or platinum oxide,in a solvent or mixture of solvents such as ethyl acetate, ethanol,isopropanol, benzene, toluene, pyridine, ethyleneglycol dimethylether,diethyleneglycol dimethylether, N—C₁₋₅-alkylmorpholine, diethyl ether,tert.-butyl-methylether, tetrahydrofuran, hexane or cyclohexane.

(c) In order to prepare a compound of general formula

wherein R³ to R⁵ are as hereinbefore defined, Z¹ denotes the hydrogenatom or a protective group, for example a C₁₋₅-alkyloxycarbonyl orbenzyloxycarbonyl group, and B′ denotes a group of formula

wherein R⁸ is as hereinbefore defined:coupling and subsequent cyclisation of a compound of general formula

wherein n and R⁸ are as hereinbefore defined, with a compound of generalformula

wherein R³ to R⁵ are as hereinbefore defined, Z¹ denotes a protectivegroup, for example a C₁₋₅-alkyloxycarbonyl or benzyloxycarbonyl group,and Z⁴ denotes a nucleofugic leaving group, for example a chlorine,bromine or iodine atom, a tosylate, triflate or mesylate group, afterwhich the protective group Z¹ is cleaved by methods known from theliterature.

The reaction sequence is conveniently carried out in a solvent ormixture of solvents such as water, ethanol, isopropanol, benzene,chlorobenzene, toluene, xylene, glycol, glycoldimethylether,diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone,tetralin, dimethylsulphoxide, sulpholane, methylene chloride,chloroform, tetrachloromethane or N-ethyl-diisopropylamine,N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine,triethylamine, pyridine, for example at temperatures between −30 and250° C., but preferably between 0 and 150° C., optionally convenientlyin the presence of bases such as potassium carbonate, sodium carbonate,sodium hydrogen carbonate, potassium-tert.-butoxide, sodium ethoxide,potassium hexamethyldisilazane, sodium hydride or lithiumdiiso-propylamide.

(d) In order to prepare a compound of general formula

wherein A, R¹ and R² are as hereinbefore defined and Q denotes a halogenatom or a hydroxy, C₁₋₄-alkoxy or C₁₋₄-acyloxy group:

-   -   i) nucleophilic substitution of a compound of general formula

A′-H,  (XIV)

-   -   wherein A′ denotes a 5- to 7-membered cycloalkyleneimino group        as mentioned hereinbefore under the definition of A, at the        aromatic group of general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the        nitrile group or a C₁₋₅-alkoxycarbonyl group, and subsequent        saponification of the nitrile or C₁₋₅-alkoxycarbonyl group Z²        and optionally further reaction of the resulting carboxyl group        to form a reactive carboxylic acid derivative of general formula        XIII.

The nucleophilic substitution is conveniently carried out in a solventor mixture of solvents such as ethanol, isopropanol, benzene,chlorobenzene, toluene, xylene, glycol, glycoldimethylether,diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone,tetralin, dimethylsulphoxide, sulpholane, methylene chloride,chloroform, tetrachloromethane or N-ethyl-diisopropylamine,N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine,triethylamine, pyridine, for example at temperatures between −30 and250° C., but preferably between 0 and 150° C., optionally convenientlyin the presence of bases such as potassium carbonate, sodium carbonate,potassium-tert.-butoxide, sodium ethoxide, potassiumhexamethyldisilazane, sodium hydride or lithium diisopropylamide.

-   -   ii) transition metal-catalysed coupling reaction of a compound        of general formula

A′-H,  (XIV)

-   -   wherein A′ denotes a 5- to 7-membered cycloalkyleneimino group        as mentioned hereinbefore under the definition of A, at the        aromatic group of general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the        nitrile group or a C₁₋₅-alkoxycarbonyl group and Z³ denotes a        chlorine, bromine or iodine atom or a triflate group, and        subsequent saponification of the nitrile or C₁₋₅-alkoxycarbonyl        group Z² and optionally further reaction of the resulting        carboxyl group to form a reactive carboxylic acid derivative of        general formula XIII.

The reaction is expediently carried out in a solvent or mixture ofsolvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane,diethyl ether, tert.-butyl-methyl-ether, ethyleneglycoldimethylether,diethyleneglycoldimethylether, sulpholane, dimethylformamide,N-methylpyrrolidinone, tetralin, dimethyl sulphoxide, methylenechloride, chloroform or tetrachloromethane, for example at temperaturesbetween −30 and 250° C., but preferably between 0 and 150° C.,conveniently in the presence of transition metal catalysts such asnickel on activated charcoal, palladium charcoal,tetrakis-(triphenylphosphine)-palladium(0),tris-(dibenzylideneacetone)-dipalladium(0), palladium(II)acetate,palladium(II)chloride, bis-(triphenylphosphine)-palladium(II)-chloride,bis-(tricyclohexylphosphine)-palladium(II)-chloride,bis-(triethylphosphine)-palladium(II)-chloride,bis-(tri-o-tolylphosphine)-palladium(II)-chloride, optionally in thepresence of ligands such as triphenylphosphine, tri-o-tolylphosphine,tri-tert.-butylphosphine, 1,3-bis-(diphenylphosphino)-propane,2,2′-bis-(diphenyl-phosphino)-1,1′-dinaphthyl,1,1′-bis-(diphenylphosphino)-ferrocene, xantphos, and conveniently inthe presence of a base such as sodium methoxide, sodium ethoxide,sodium-tert.-butoxide, potassium-tert.-butoxide,sodium-tert.-butyldimethyl-silanoate, potassium hexamethyldisilazane,lithium diisopropylamide, potassium carbonate, rubidium carbonate,caesium carbonate, potassium phosphate, sodium hydride, optionally inthe presence of a complexing agent such as 18-crown-6-ether as well asconveniently using an inert gas atmosphere (for example nitrogen orargon) and optionally under pressure.

-   -   iii) Selective oxidation of a cycloalkyleneimino group in        compounds of general formula

-   -   wherein A′ denotes a 5- to 7-membered, optionally also        substituted, 2-oxo-cycloalkyleneimine group as mentioned        hereinbefore under the definition of A, R¹ and R² are as        hereinbefore defined and Z² denotes the carboxyl group, and        optionally further reacting to form a reactive carboxylic acid        derivative of general formula XIII.

The reaction of a compound of general formula XIII obtained for exampleby the processes described hereinbefore, wherein A′ denotes acycloalkyleneimino group and Q denotes the hydroxy group, to form thecorresponding lactam by oxidation of a methylene group adjacent to thenitrogen is carried out for example with oxidising agents such aspotassium permanganate, potassium chromate, potassium dichromate,chromium(VI)oxide, mercury (II)chloride, selenium(IV)oxide, lead(IV)oxide, lead (II,IV)oxide, potassium peroxomonosulphate, hydrogenperoxide, sodium hypochlorite, optionally in the presence of a suitablecatalyst such as nickel(II)chloride, cobalt(II)chloride,ruthenium(III)chloride, osmium(VIII)oxide, vanadium(IV)oxide and/or inthe presence of a crown ether such as 18-crown-6, in a solvent ormixture of solvents such as water, formic acid, acetic acid, ethylacetate, benzene, pyridine, dichloromethane, chloroform,tetrachloromethane, optionally under 2-phase conditions in the presenceof a suitable phase transfer catalyst such as for exampletetrabutylammonium chloride, tetrabutylammonium bromide,benzyl-triethyl-ammonium chloride or methyl-trioctyl-ammonium chloride,optionally in the presence of an acid such as acetic acid, hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, sodium hydrogensulphate, sodium dihydrogen phosphate and/or a base such as sodiumhydroxide, potassium hydroxide, ammonia, pyridine, potassium phosphate,dipotassium hydrogen phosphate or sodium acetate at temperatures between−30 and 250° C., but preferably between 0 and 150° C. For example thisreaction may be carried out as described by J. H. Markgraf, C. A.Stickney, J. Heterocycl. Chem. 2000, 37(1), 109.

-   -   iv) transition metal-catalysed coupling reaction of a compound        of general formula

A′-H,  (XIV)

-   -   wherein A′ denotes a 5- to 7-membered, optionally substituted        2-oxo-cycloalkyleneimino group as mentioned hereinbefore under        the definition of A, at the aromatic group of general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the        nitrile group or a C₁₋₅-alkoxycarbonyl group and Z³ denotes a        chlorine, bromine or iodine atom or a triflate group, and        subsequent saponification of the nitrile or C₁₋₅-alkoxycarbonyl        group Z² and optionally further reaction of the resulting        carboxyl group to form a reactive carboxylic acid derivative of        general formula XII.

The reaction is expediently carried out in a solvent or mixture ofsolvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane,diethyl ether, tert.-butyl-methyl-ether, ethyleneglycoldimethylether,diethyleneglycoldimethylether, sulpholane, dimethylformamide,N-methylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride,chloroform or tetrachloromethane, for example at temperatures between−30 and 250° C., but preferably between 0 and 200° C., conveniently inthe presence of transition metal catalysts such astetrakis-(triphenylphosphine)-palladium(0),tris-(dibenzylideneacetone)-dipalladium(0), palladium(II)acetate,palladium(II)chloride, bis-(triphenylphosphine)-palladium(II)-chloride,bis-(tricyclohexylphosphine)-palladium(II)-chloride,bis-(triethylphosphine)-palladium(II)-chloride,bis-(tri-o-tolylphosphine)-palladium(II)-chloride, optionally in thepresence of ligands such as triphenylphosphine, tri-o-tolylphosphine,tri-tert.-butylphosphine, 1,3-bis-(diphenylphosphino)-propane,2,2′-bis-(diphenylphosphino)-1,1′-dinaphthyl,1,1′-bis-(diphenylphosphino)-ferrocene, xantphos, or for example in thepresence of a transition metal catalyst such as copper(I)-iodide,copper(I)-bromide or copper(I)-acetate and conveniently in the presenceof a base such as tetramethylguanidine, tetramethylethylenediamine orN,N′-dimethylethylenediamine and conveniently in the presence of a basesuch as sodium methoxide, sodium ethoxide, sodium-tert.-butoxide,potassium-tert.-butoxide, sodium-tert.-butyldimethyl-silanoate,potassium hexamethyldisilazane, lithium diisopropylamide, potassiumcarbonate, rubidium carbonate, caesium carbonate, potassium phosphate,sodium hydride, optionally in the presence of a complexing agent such as18-crown-6-ether and conveniently using an inert gas atmosphere (forexample nitrogen or argon) and optionally under pressure.

-   -   v) Acylation/sulphonylation and alkylation of a compound of        general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the        nitrile group or a C₁₋₅-alkoxycarbonyl group, with a compound of        general formula

-   -   wherein E denotes a carbonyl, oxycarbonyl, sulphonyl or a        sulphamoyl group optionally substituted at the nitrogen atom as        mentioned hereinbefore, G denotes a chlorine, bromine or iodine        atom or an anhydride, C₁₋₅-alkoxy or benzotriazoloxy group or E        and G together denote an isocyano group and Z⁴ denotes a        nucleofugic leaving group, for example a chlorine, bromine or        iodine atom, a tosylate, triflate or mesylate group, and n is a        number between 3 and 5, while individual methylene groups        according to the description mentioned hereinbefore may        additionally be substituted or replaced by heteroatoms, and        subsequent intramolecular cyclisation by alkylation of the        anilide nitrogen while cleaving the nucleofugic leaving group        Z⁴, followed by saponification of the nitrile or        C₁₋₅-alkoxycarbonyl group Z² and optionally further reaction of        the resulting carboxyl group to form a reactive carboxylic acid        derivative of general formula XIII.

The acylation/sulphonylation is conveniently carried out in a solvent ormixture of solvents such as benzene, chlorobenzene, toluene, xylene,glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide,N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane,methylene chloride, chloroform, tetrachloromethane,N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine,N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine,pyridine, for example at temperatures between −30 and 250° C., butpreferably between 0 and 150° C., conveniently in the presence of basessuch as pyridine, triethylamine, p-dimethylaminopyridine, potassiumcarbonate, sodium carbonate, potassium-tert.-butoxide, sodium methoxide,sodium ethoxide or basic ion exchanger.

The subsequent intramolecular alkylation is conveniently carried out ina solvent or mixture of solvents such as benzene, chlorobenzene,toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether,dimethylformamide, dimethylsulphoxide, sulpholane, methylene chloride,tetrachloromethane, N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine,N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine,pyridine, for example at temperatures between −30 and 250° C., butpreferably between 0 and 150° C., conveniently in the presence of basessuch as pyridine, triethylamine, potassium carbonate, sodium carbonate,potassium-tert.-butoxide, sodium methoxide, sodium ethoxide, sodiumhydride, potassium hexamethyldisilazane or lithium diisopropylamide.

-   -   vi) carbamoylation/urea formation with a compound of general        formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the        nitrile group or a C₁₋₅-alkoxycarbonyl group, and which may be        obtained by methods known from the literature from compounds of        general formula XVIII, for example by reaction with phosgene in        toluene, with a compound of general formula

-   -   wherein Z⁴ denotes a nucleofugic leaving group, for example a        chlorine, bromine or iodine atom, a tosylate, triflate or        mesylate group, and E denotes a hydroxyl, amino or        C₁₋₃-alkylamino function and n is a number between 2 and 4,        while individual methylene groups may additionally be        substituted according to the description mentioned hereinbefore,        and subsequent intra-molecular cyclisation by alkylation of the        anilide nitrogen while cleaving the nucleofugic leaving group        Z⁴, followed by saponification of the nitrile or        C₁₋₅-alkoxycarbonyl group Z² and optionally further reaction of        the resulting carboxyl group to form a reactive carboxylic acid        derivative of general formula XIII.

The carbamoylation is conveniently carried out in a solvent or mixtureof solvents such as benzene, chlorobenzene, toluene, xylene,glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide,N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane,methylene chloride, chloroform, tetrachloromethane,N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine,N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine,pyridine, for example at temperatures between −30 and 250° C., butpreferably between 0 and 150° C. The subsequent intramolecularalkylation is carried out for example analogously to the methoddescribed under v).

-   -   vii) cyclisation metathesis of a compound of general formula

-   -   wherein R¹ and R² are defined as described hereinbefore, Z²        denotes a nitrile, C₁₋₅-alkoxycarbonyl or carboxyl group, E        denotes an aminocarbonyl, aminosulphonyl or amino group        optionally substituted according to the description mentioned        hereinbefore or a carbonyl or sulphonyl group or an oxygen or        sulphur atom or a bond, while m and o independently of one        another denote identical or different numbers between 1 and 3        which may be obtained by a sequence of alkylation and        acylation/sulphonylation/carbamoylation/sulphamoylation with        corresponding reagents by the methods already described herein        or known from the literature, followed by saponification of the        nitrile or C₁₋₅-alkoxycarbonyl group Z² and optionally further        reaction of the resulting carboxyl group to obtain a reactive        carboxylic acid derivative of general formula XIII.

The cyclisation by a reaction of metathesis is conveniently carried outin a solvent or mixture of solvents such as benzene, chlorobenzene,toluene, xylene, methanol, ethanol, propanol, diethyl ether,tert.-butyl-methyl-ether, tetrahydrofuran, dioxane, glycoldimethylether,diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone,tetralin, dimethylsulphoxide, sulpholane, methylene chloride,chloroform, tetrachloromethane, pyridine, in the presence of a catalystsuch as benzylidene-bis-(tricyclohexylphosphine)-dichloro-ruthenium (1stgeneration Grubbs catalyst) orbenzylidene-[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium(2nd generation Grubbs catalyst) for example at temperatures between −30and 250° C., but preferably between 0 and 150° C., conveniently under aninert gas atmosphere, for example argon.

(e) In order to prepare a compound of general formula

wherein A, B and R¹ to R⁵ are as hereinbefore defined:acylation of a compound of general formula

wherein B and R³ to R⁵ are as hereinbefore defined and Z¹ denotes thehydrogen atom,with a carboxylic acid or a reactive carboxylic acid derivative ofgeneral formula

wherein A, R¹ and R² are as hereinbefore defined and Q denotes a hydroxyor C₁₋₄-alkoxy group, a halogen atom or an acyloxy group.

The acylation is conveniently carried out with a corresponding halide oranhydride in a solvent such as methylene chloride, chloroform, carbontetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene,acetonitrile, dimethylformamide, sodium hydroxide solution orsulpholane, optionally in the presence of an inorganic or organic baseat temperatures between −20 and 200° C., but preferably at temperaturesbetween −10 and 160° C.

The acylation may, however, also be carried out with the free acid,optionally in the presence of an acid-activating agent or a dehydratingagent, e.g. in the presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, hydrogen chloride, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,phosphorus pentoxide, N,N-dicyclohexyl carbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole, N,N′-carbonyldiimidazole,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate/N-methylmorpholine,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate/N-ethyldiisopropylamine,apentafluorophenyl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate/triethylamine, N,N′-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, at temperatures between −20 and200° C., but preferably at temperatures between −10 and 160° C.

Other methods of amide coupling are described for example in P. D.Bailey, I. D. Collier, K. M. Morgan in “Comprehensive Functional GroupInterconversions”, Vol. 5, page 257ff, Pergamon 1995.

-   (f) In order to prepare a compound of general formula (II), (XXIV),    (VII), (VIII), (XI) or (XXIII), wherein A, B and R¹ to R⁷ are as    hereinbefore defined and R⁸ denotes a C₂₋₃-alkynyl group which is    linked to the aromatic group via the carbon atom, and which    simultaneously carries the triple bond, from a corresponding    compound wherein R⁸ denotes a bromine or iodine atom or the    triflate, boric acid or boric acid ester group:    transition metal-catalysed coupling reaction of a compound of    general formula

wherein Z⁵ denotes the hydrogen atom, the methyl group or a protectivegroup such as for example a trimethylsilyl, tert.-butyl-dimethylsilyl,tert.-butyl-diphenylsilyl or triisopropyl group, which can then becleaved,with a compound of general formula (II), (XXIV), (VII), (VIII), (XI) or(XXIII), wherein A, B and R¹ to R⁷ are as hereinbefore defined and R⁸denotes a bromine or iodine atom or the triflate, boric acid or boricacid ester group.

The reaction is preferably carried out in a solvent or mixture ofsolvents such as acetonitrile, diethyl ether, tetrahydrofuran, dioxane,water or dimethylformamide or a mixture of solvents in the presence of apalladium catalyst such as for examplebis(triphenylphosphine)-palladium(II)chloride,palladium(II)-[1,1′-bis-(diphenylphosphino)ferrocene]-chloride ortetrakis-(triphenylphosphine)-palladium(0) in the presence of a basesuch as triethylamine, N-isopropyl-diethylamine,N,N-diisopropyl-ethylamine, potassium-tert.-butoxide, sodium carbonateor caesium carbonate, optionally in the presence of ligands such astriphenylphosphine, tri-o-tolylphosphine, tri-tert.-butylphosphine,1,3-bis-(diphenylphosphino)-propane,2,2′-bis-(diphenylphosphino)-1,1′-dinaphthyl,1,1′-bis-(diphenylphosphino)-ferrocene, xantphos and optionally in thepresence of a transition metal compound such as a copper halide such asfor example copper(I)iodide and at temperatures between 20 and 120° C.,preferably at temperatures between 20 and 90° C. under argon or nitrogenatmosphere (cf. also K. Sonogashira, Comprehensive Organic Synthesis,Vol. 3, page 52ff., Pergamon Press, Oxford 1991).

Any silyl protective group present such as for example trimethylsilyl ispreferably cleaved in a solvent or mixture of solvents such as water,methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran ordimethylformamide in the presence of a base such as lithium hydroxide,sodium hydroxide, potassium carbonate or sodium methoxide. For cleavingin organic solvents such as for example diethyl ether, tetrahydrofuran,dimethylformamide or dichloromethane it is also possible to use fluoridereagents, such as for example tetrabutylammonium fluoride, lithiumfluoride or potassium fluoride, optionally with the addition of acomplexing agent such as 18-crown-6-ether.

In the reactions described above any reactive groups present such ashydroxy, carboxy, amino, alkylamino or imino groups may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction. For example, a suitable protecting group for ahydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl,benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,

suitable protecting groups for a carboxyl group might be thetrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup,suitable protecting groups for an amino, alkylamino or imino group mightbe the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group and additionally, for the amino group, thephthalyl group.

Other protective groups and their cleaving are described in T. W.Greene, P. G. M. Wuts, “Protecting Groups in Synthesis”, Wiley, 1991 and1999.

Any protecting group used may optionally subsequently be cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide or by ethersplitting, e.g. in the presence of iodotrimethylsilane, at temperaturesbetween 0 and 100° C., preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleavedhydrogenolytically, for example, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat ambient temperature, and at a hydrogen pressure of 1 to 7 bar,preferably, however, 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

A methoxy group is expediently cleaved in the presence of borontribromide in a solvent such as methylene chloride at temperaturesbetween −35 and −25° C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroaceticacid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

An allyloxycarbonyl group is cleaved by treating with a catalytic amountof tetrakis-(triphenylphosphine)-palladium(0), preferably in a solventsuch as tetrahydrofuran and preferably in the presence of an excess of abase such as morpholine or 1,3-dimedone at temperatures between 0 and100° C., preferably at ambient temperature and under an inert gas, or bytreating with a catalytic amount oftris-(triphenylphosphine)-rhodium(I)chloride in a solvent such asaqueous ethanol and optionally in the presence of a base such as1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70° C.

Compounds of general formulae (II), wherein the group B′ is representedby a group of general formula (III), and (IV) may be prepared forexample analogously to K. Maekawa, J. Ohtani, Agr. Biol. Chem. 1976, 40,791-799.

Moreover the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained whichoccur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides may be a (+)- or(−)-menthyloxycarbonyl, for example.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaricacid, succinic acid, lactic acid, citric acid, tartaric acid or maleicacid.

Moreover, if the new compounds of formula I contain a carboxy group,they may subsequently, if desired, be converted into the salts thereofwith inorganic or organic bases, particularly for pharmaceutical useinto the physiologically acceptable salts thereof. Suitable bases forthis purpose include for example sodium hydroxide, potassium hydroxide,cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned, the compounds of general formula I as well as thetautomers, the enantiomers, the diastereomers and the physiologicallyacceptable salts thereof have valuable pharmacological properties,particularly an antithrombotic activity, which is preferably based on aneffect on thrombin or factor Xa, for example on a thrombin-inhibiting orfactor Xa-inhibiting activity, on a prolonging effect on the aPTT timeand/or on an inhibiting effect on related serine proteases such as e.g.urokinase, factor Vila, factor IXa, factor Xla and factor XIIa.

The compounds listed in the experimental section were investigated fortheir effect on the inhibition of factor Xa as follows:

Method:

Enzyme-kinetic measurement with chromogenic substrate. The quantity ofp-nitroaniline (pNA) released from the colourless chromogenic substrateby human factor Xa is determined photometrically at 405 nm. It isproportional to the activity of the enzyme used. The inhibition of theenzyme activity by the test substance (in relation to the solventcontrol) is determined at various concentrations of test substance andfrom this the IC₅₀ is calculated, as the concentration which inhibitsthe factor Xa used by 50%.

Material:

Tris(hydroxymethyl)-aminomethane buffer (100 mMol) and sodium chloride(150 mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-freeFactor Xa (Calbiochem), spec. activity: 217 IU/mg, final concentration:7 IU/ml for each reaction mixture

Substrate S 2765 (Chromogenix), final concentration: 0.3 mM/I (1 KM) foreach reaction mixtureTest substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03,0.01, 0.003, 0.001 μMol/l

Procedure:

10 μl of a 23.5-times concentrated starting solution of the testsubstance or solvent (control), 175 ml of TRIS/HSA buffer and 25 μl of a65.8 U/L Factor Xa working solution are incubated for 10 minutes at 37°C. After the addition of 25 μl of S 2765 working solution (2.82 mMol/l)the sample is measured in a photometer (SpectraMax 250) at 405 nm for600 seconds at 37° C.

Evaluation:

1. Determining the maximum increase (deltaOD/minutes) over 21 measuringpoints.2. Determining the % inhibition based on the solvent control.3. Plotting a dosage/activity curve (% inhibition vs substanceconcentration).4. Determining the IC₅₀ by interpolating the X-value (substanceconcentration) of the dosage/activity curve at Y=50% inhibition.

All the compounds tested had an IC₅₀ value of less than 100 μmol/L.

The compounds prepared according to the invention are generally welltolerated.

In view of their pharmacological properties the new compounds and thephysiologically acceptable salts thereof are suitable for the preventionand treatment of venous and arterial thrombotic diseases, such as forexample the prevention and treatment of deep leg vein thrombosis, forpreventing reocclusions after bypass operations or angioplasty (PT(C)A),and occlusion in peripheral arterial diseases, and for preventing andtreating pulmonary embolism, disseminated intravascular coagulation andsevere sepsis, for preventing and treating DVT in patients withexacerbation of COPD, for treating ulcerative colitis, for treating andpreventing coronary thrombosis, for preventing stroke and the occlusionof shunts. In addition, the compounds according to the invention aresuitable for antithrombotic support in thrombolytic treatment, such asfor example with alteplase, reteplase, tenecteplase, staphylokinase orstreptokinase, for preventing long-term restenosis after PT(C)A, for theprevention and treatment of ischaemic incidents in patients with allforms of coronary heart disease, for preventing metastasis and thegrowth of tumours and inflammatory processes, e.g. in the treatment ofpulmonary fibrosis, for preventing and treating rheumatoid arthritis,for preventing and treating fibrin-dependent tissue adhesions and/or theformation of scar tissue and for promoting wound healing processes. Thenew compounds and the physiologically acceptable salts thereof may beused therapeutically in conjunction with acetylsalicylic acid, withinhibitors of platelet aggregation such as fibrinogen receptorantagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), withphysiological activators and inhibitors of the clotting system and therecombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), withinhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine),with P₂T receptor antagonists (e.g. cangrelor) or with combinedthromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

The dosage required to achieve such an effect is appropriately 0.01 to 3mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each caseadministered 1 to 4 times a day.

For this purpose, the compounds of formula I prepared according to theinvention may be formulated, optionally together with other activesubstances, with one or more inert conventional carriers and/ordiluents, e.g. with corn starch, lactose, glucose, microcrystallinecellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol,water/polyethylene glycol, propylene glycol, cetylstearyl alcohol,carboxymethylcellulose or fatty substances such as hard fat or suitablemixtures thereof, to produce conventional galenic preparations such asplain or coated tablets, capsules, powders, suspensions orsuppositories.

The Examples which follow are intended to illustrate the inventionwithout restricting its scope:

Experimental Section

As a rule, melting points, IR, UV, ¹H-NMR and/or mass spectra have beenobtained for the compounds prepared. Unless otherwise stated, R_(f)values were obtained using ready-made silica gel 60 F₂₅₄ TLC plates (E.Merck, Darmstadt, Item no. 1.05714) without chamber saturation. TheR_(f) values obtained under the name Alox were determined usingready-made aluminium oxide 60 F₂₅₄ TLC plates (E. Merck, Darmstadt, Itemno. 1.05713) without chamber saturation. The R_(f) values obtained underthe name Reversed-phase-8 were determined using ready-made RP-8_(F254s)TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chambersaturation. The ratios given for the eluants refer to units by volume ofthe solvent in question. Chromatographic purification was done usingsilica gel supplied by Messrs Millipore (MATREX™, 35-70 μm). If theconfiguration is not specified in detail, it is unclear whether thecompound in question is a pure stereoisomer or a mixture of enantiomerand diastereomer.

The following abbreviations are used in the descriptions of the tests:

-   Boc tert.-butoxycarbonyl-   DIPEA N-ethyl-diisopropylamine-   DMSO dimethylsulphoxide-   DMF N,N-dimethylformamide-   sat. saturated-   h hour(s)-   i. vac. in vacuo-   conc. concentrated-   NMM N-methyl-morpholine-   NMP N-methyl-pyrrolidin-2-one-   o ortho-   PfTU O-pentafluorophenyl-N,N,N′,N′-etramethyluronium    hexafluorophosphate-   PPA propanephosphonic cycloanhydride-   quant. quantitative-   R_(f) retention factor-   R_(t) retention time-   rac. racemic-   TBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   tert. tertiary-   Σ yield over all the steps carried out analogously as described

The HPLC/MS data for Examples 35 to 38 were obtained under the followingconditions:

(a) Waters ZMD, Alliance 2690 HPLC, Waters 2700 Autosampler, Waters 996diode array detectorThe following was used as the mobile phase:A: water with 0.1% trifluoroacetic acidB: acetonitrile with 0.1% trifluoroacetic acid

time in min % A % B flow rate in ml/min 0.0 95 5 1.00 0.1 95 5 1.00 5.12 98 1.00 6.5 2 98 1.00 7.0 95 5 1.00

The stationary phase used was a Waters column X-Terra™ MS O₁₈ 3.5 μm,4.6 mm×50 mm (column temperature: constant at 25° C.)

The diode array detection took place in a wavelength range from 210-500nm Range of mass-spectrometry detection: m/z 120 to m/z 950

(b) The HPLC/MS data for the other Examples, if provided, were obtainedunder the following conditions:HP 1100 with quarternary pump, Gilson G215 Autosampler, HP diode arraydetector.

The mobile phase used was:

A: water with 0.1% TFAB: acetonitrile with 0.08% TFA

time in min % A % B flow rate in ml/min 0.0 95 5 0.4 0.15 95 5 0.4 4.652 98 0.4 6.0 2 98 0.4 6.5 95 5 0.4The stationary phase used was a Waters column X-Terra™ MS C₁₈ 2.5 μm,2.1 mm×50 mm (column temperature: constant at 25° C.)

The diode array detection took place in a wavelength range from 210-550nm Range of mass-spectrometry detection: m/z 120 to m/z 1000.

EXAMPLE 13-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-benzamide

(a) 4-(4-N-acetyl-[1,4]diazepan-1-yl)-3-chloro-benzonitrile

4.67 g (30 mmol) 3-chloro-4-fluoro-benzonitrile and 4.27 g (30 mmol)N-1-acetyl-[1,4]diazepan are stirred in 5.0 ml DIPEA for 6 hours at 90°C. Then the mixture is evaporated down i. vac. and the residue isdissolved in dichloromethane. The organic phase is washed twice withwater, dried over sodium sulphate and evaporated down i. vac. Theresidue is further reacted without any more purification.

Yield: 7.50 g (90%)

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=50:1)

(b) 3-chloro-4-([1,4]diazepan-1-yl)-benzoic acid

The residue obtained in Example 1a (7.50 g, 27.0 mmol) is refluxed for 8h in 50 ml 25% potassium hydroxide solution. Then the mixture isadjusted to pH 5 with conc. hydrochloric acid. The solid precipitated isfiltered off, dried and further reacted without any more purification.

Yield: 5.60 g (81%)

R_(f) value: 0.0 (silica gel; dichloromethane/ethanol=9:1)

(c) methyl 3-chloro-4-([1,4]diazepan-1-yl)-benzoate

The residue obtained in Example 1b (3.00 g, 11.8 mmol) is suspended in100 ml of methanol and hydrogen chloride is piped in over 1 hour withstirring and heating to reflux temperature. Then the mixture isevaporated down i. vac., the residue is combined with 5% sodium hydrogencarbonate solution and extracted 3 times with dichloromethane. Thecombined organic phases are dried over sodium sulphate. The residueremaining after evaporation i. vac. is further reacted without any morepurification.

Yield: 2.25 g (71%)

R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=4:1+2% ammonia)

C₁₃H₁₇ClN₂O₂ (268.75)

Mass spectrum: (M+H)⁺=269/271 (chlorine isotope)

(d) methyl 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoate

The residue obtained in Example 1c (1.00 g, 3.72 mmol) is combined with0.53 g (3.80 mmol) potassium carbonate in 10 ml dichloromethane and then0.83 g (3.80 mmol) di-tert. butyl pyrocarbonate are added dropwise. Thenthe mixture is stirred for 16 hours at ambient temperature. Then it isdiluted with dichloromethane, washed twice with water, dried over sodiumsulphate and evaporated down i. vac. Purification by chromatography onsilica gel is then carried out (eluant: methylene chloride/ethanol99:1).

Yield: 1.34 g (98%)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=50:1)

C₁₈H₂₅ClN₂O₄ (368.86)

Mass spectrum: (M+H)⁺=369/371 (chlorine isotope)

(e) 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoic acid

0.60 g (1.63 mmol) methyl4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoate are dissolved in 10 mlof methanol, combined with 4 ml 2-molar potassium hydroxide solution andstirred for 3 hours at 40° C. Then the mixture is evaporated down i.vac., the residue is diluted with distilled water, acidified withsaturated potassium hydrogen sulphate solution and extracted 3 timeswith ethyl acetate. The combined organic phases are dried over sodiumsulphate and concentrated by evaporation. The residue is further reactedwithout any more purification.

Yield: 0.50 g (87%)

R_(f) value: 0.05 (silica gel; dichloromethane/ethanol=50:1)

C₁₇H₂₃ClN₂O₄ (354.84)

(f)4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide

532 mg (1.50 mmol) 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoic acidare suspended in 15 ml THF and after the addition of 546 mg (1.70 mmol)TBTU and 646 mg (5.0 mmol) DIPEA stirred for 30 minutes at ambienttemperature. Then 403 mg (1.50 mmol)(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-dihydrochloride areadded and the mixture is stirred for a further 16 hours at ambienttemperature. It is then evaporated down i. vac., the residue isdissolved in ethyl acetate, the organic phase is washed with 5% sodiumhydrogen carbonate solution and water and dried over sodium sulphate.After evaporation i. vac. the residue remaining is purified bychromatography on silica gel (eluting gradient: petroleum ether/ethylacetate: 90:10->60:40).

Yield: 630 mg (79%)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=19:1)

C₂₆H₃₁Cl₂N₅O₃ (532.48)

Mass spectrum: (M+H)⁺=532/534/536 (chlorine isotope)

(g)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-benzamide

A solution of 610 mg (1.15 mmol)4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamidein 30 ml dichloromethane is combined with 3 ml TFA and stirred for 3hours at ambient temperature. Then it is evaporated down i. vac., theresidue is taken up in ethyl acetate, washed with 5% sodium hydrogencarbonate solution and water and dried over sodium sulphate. Afterevaporation i. vac. the residue is purified by chromatography on silicagel (eluting gradient: petroleum ether/ethyl acetate 80:20->50:50).

Yield: 380 mg (77%)

R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=9:1)

C₂₁H₂₃Cl₂N₅O (432.36)

Mass spectrum: (M+H)⁺=432/434/436 (chlorine isotope)

The following compound was prepared analogously:

structural formula No. Name yield mass peak(s) R_(f) value/R_(t) value115

Σ: 13% (M + H)⁺ = 462/464/466 (chlorine isotope) 0.13 (silica gel,dichloromethane/ methanol = 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-([1,4]-diazepan-1-yl)-benzamide

EXAMPLE 24-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide

(a) 4-(piperazin-1-yl)-3-trifluoromethyl-benzoic acid

37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with12.4 g (66 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile suspended in 40ml of ethanol. Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and13.7 ml of water are added and the mixture is refluxed for a further 3.5hours and kept at ambient temperature for a further 15 hours. Then 43.5ml of conc. hydrochloric acid are added and the mixture is cooled to 10°C. for 30 minutes with stirring. The precipitate obtained is suctionfiltered, washed with a little water and dried at 40° C. in thecirculating air dryer for 24 hours.

Yield: 20.8 g (quantitative)

(b) methyl 4-(piperazin-1-yl)-3-trifluoromethyl-benzoate

5.00 g (18.2 mmol) 4-(piperazin-1-yl)-3-trifluoromethyl-benzoic acid arestirred 16 hours in 50 ml of methanolic hydrochloric acid. Afterevaporation of the reaction mixture i. vac. the residue is stirred withisopropanol. The solid is filtered off, washed with diethyl ether anddried at 60° C. in the circulating air dryer.

Yield: 5.00 g (76%)

C₁₃H₁₅F₃N₂O₂*2HCl (288.27/361.19)

Mass spectrum: (M+H)⁺=289

R_(f) value: 0.58 (silica gel;cyclohexane/dichloromethane/methanol=70:15:15+2% conc. ammonia solution)

(c) methyl 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoate

5.77 g (11.78 mmol) methyl 4-(piperazin-1-yl)-3-trifluoromethyl-benzoateare placed in 100 ml THF and combined with 4.47 g (20.5 mmol) di-tert.butyl pyrocarbonate. After 40 hours stirring at ambient temperatureunder a nitrogen atmosphere the reaction mixture is evaporated down i.vac., the residue is combined with water and sat. sodium chloridesolution and extracted with ethyl acetate. The combined organic phasesare washed with water, semisaturated and sat. sodium chloride solution,dried over magnesium sulphate and evaporated down i. vac. The residue ispurified by chromatography on silica gel (eluting gradient: petroleumether/ethyl acetate 9:1->8:1).

Yield: 2.60 g (34%)

R_(f) value: 0.52 (silica gel; petroleum ether/ethyl acetate 7:3+1%conc. ammonia solution)

C₁₈H₂₃F₃N₂O₄ (388.39)

Mass spectrum: (M+H)⁺=389

(d) 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid

2.60 g (6.69 mmol) methyl4-(4-N-tert.-butoxylcarbonyl-piperazin-1-yl)-3-trifluoromethyl-benzoateare dissolved in 10 ml of methanol and combined with 12.3 ml (12.3 mmol)1-molar sodium hydroxide solution. After 15 minutes a further 10 ml ofmethanol are added and the reaction mixture is stirred for 42 hours atambient temperature. Then the mixture is evaporated down i. vac., theresidue is combined with ice and acidified with acetic acid. Theprecipitate obtained is suction filtered, washed with water and dried inthe circulating air dryer at 50° C. and in the drying pistol at 40° C.over KOH and SiO₂.

Yield: 2.40 g (96%)

R_(f) value: 0.41 (silica gel; petroleum ether/ethyl acetate=1:1+1%acetic acid)

C₁₇H₂₁F₃N₂O₄ (374.36)

Mass spectrum: (M−H)⁻=373

(e)4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide

Prepared analogously to Example 1f from4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid, TBTU, NMM and(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in NMP and subsequentpurification by chromatography on silica gel (eluant: petroleumether/ethyl acetate=50:50).

Yield: 57%

R_(f) value: 0.20 (silica gel; petroleum ether/ethyl acetate=1:1)

C₂₆H₂₉ClF₃N₅O₃ (552.00)

Mass spectrum: (M+H)⁺=552/554 (chlorine isotope)

EXAMPLE 3N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide

Prepared analogously to Example 1g from4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamideand TFA in dichloromethane.

Yield: 73%

R_(f) value: 0.28 (silica gel; dichloromethane/methanol=90:10+ammoniasolution)

C₂₁H₂₁ClF₃N₅O*2 CF₃COOH (679.93/451.88)

Mass spectrum: (M+H)⁺=452/454 (chlorine isotope)

The following were prepared analogously to the sequence described inExamples 2 and 3:

structural formula No. Name yield mass peak(s) R_(f) value  4

Σ: 14% (M + H)⁺ = 482/484 (chlorine isotope) 0.15 (silica gel,CH₃COOC₂H₅/ C₂H₅OH 9:1 + NH₃)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide 40

Σ: 13% (M + H)⁺ = 512/514 (chlorine isotope) 0.20 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1S)-1-(5-chloro-1H-benzmidazol-2-yl)-3-methylsulphanyl-propyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide

EXAMPLE 54-(4-N-acetyl-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide

220 mg (0.32 mmol)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide-ditrifluoroacetatein 5 ml THF are combined with 0.23 ml (1.65 mmol) TEA, 50 μl (0.70 mmol)acetylchloride are added dropwise with stirring and cooling in the icebath and stirred for 2 hours at ambient temperature. The reactionmixture is poured into ice water and then extracted with ethyl acetate.The organic phase is washed with water and sat. sodium chloridesolution, dried over sodium sulphate and evaporated down i. vac. Theresidue is triturated with a solvent mixture of ethyl acetate anddiethyl ether, filtered off, washed with diethyl ether and dried in adrying pistol at 50° C.

Yield: 0.13 g (81%)

R_(f) value: 0.55 (silica gel; dichloromethane/ethanol=9:1+ammoniasolution)

C₂₃H₂₃ClF₃N₅O₂ (493.92)

Mass spectrum: (M+H)⁺=494/496 (chlorine isotope)

EXAMPLE 64-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide

(a) methyl 4-(6-bromo-hexanoyl-amino)-3-methyl-benzoate

A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF isslowly added dropwise with stirring at ambient temperature to 1.65 g (10mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA.After 16 hours stirring at ambient temperature the mixture is evaporateddown i. vac., the residue is dissolved in dichloromethane, washed twicewith water and dried over sodium sulphate. The residue remaining afterevaporation i. vac. is further reacted without any more purification.

Yield: 3.30 g (96%)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=4:1)

C₁₅H₂₀BrNO₃ (342.24)

(b) methyl 4-(azepan-2-on-1-yl)-3-methyl-benzoate

3.20 g (9.35 mmol) of the product obtained in Example 5a is refluxed for4 hours in a freshly prepared solution of 1.00 g (43.5 mmol) sodium in80 ml of methanol. Then the mixture is evaporated down i. vac., theresidue is acidified with 2-molar acetic acid and extracted with ethylacetate. The combined organic phases are washed with water and driedover sodium sulphate. The residue obtained after evaporation i. vac. isfurther reacted without any more purification.

Yield: 1.90 g (contaminated product)

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=50:1)

C₁₅H₁₉NO₃ (261.32)

Mass spectrum: (M+H)⁺=262

(c) 4-(azepan-2-on-1-yl)-3-methyl-benzoic acid

1.90 g of the product obtained in Example 5b in 30 ml of methanol iscombined with 10 ml 2-molar sodium hydroxide solution and stirred for 16hours at ambient temperature. After evaporation i. vac. the residue iscombined with water and acidified with conc. hydrochloric acid. Theprecipitate formed is filtered off and dried. After dissolving inmethanol and applying to silica gel the product is purified bychromatography on silica gel (eluting gradient: petroleum ether/ethylacetate 70:30->50:50).

Yield: 0.23 g (10% over 2 steps)

R_(f) value: 0.10 (silica gel; petroleum ether/ethyl acetate=1:2)

C₁₄H₁₇NO₃ (247.30)

Mass spectrum: (M+H)⁺=248

(d)4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide

Prepared analogously to Example 1f from4-(azepan-2-on-1-yl)-3-methyl-benzoic acid, TBTU, DIPEA and(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in THF and subsequentpurification by chromatography on silica gel (eluting gradient: ethylacetate/ethanol 95:5->90:10).

Yield: 61%

R_(f) value: 0.30 (silica gel; ethyl acetate)

C₂₃H₂₅ClN₄O₂ (424.93)

Mass spectrum: (M+H)⁺=425/427 (chlorine isotope)

The following compounds were prepared analogously:

structural formula No. Name yield mass peak(s) R_(f) value  7

Σ: 1.1% (M − H)⁻ = 453/455 (chlorine isotope) 0.60 (aluminum oxide,CH₂Cl₂/ C₂H₅OH 19:1)4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-benzamide 8

Σ: 7.6% (M + H)⁺ = 441/443 (chlorine isotope) 0.20 (silica gel, CH₂Cl₂/C₂H₅OH 19:1)4-(azepan-2-on-1-yl)-N-[(1R)-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide10

Σ: 72% (M + H)⁺ = 397/399 (chlorine isotope) 0.50 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide11

Σ: 24% (M + H)⁺ = 457/459 (chlorine isotope) 0.63 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide

EXAMPLE 9N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1-yl)-benzamide

(a) 4-(pyrrolidin-2-on-1-yl)-benzoic acid

19.2 g (140 mmol) 4-amino-benzoic acid are refluxed for 20 hourstogether with 25.8 ml (180 mmol) ethyl 4-bromobutyrate in 100 ml DMF.After evaporation i. vac. the residue is combined with 100 ml of waterand 50 ml petroleum ether and vigorously stirred for 50 minutes. Theprecipitate is filtered off, recrystallised from ethanol and dried at80° C.

Yield: 9.36 g (33%)

C₁₁H₁₁NO₃ (205.22)

Mass spectrum: (M+H)⁺=206

(b)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(byrrolidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from 4-(pyrrolidin-2-on-1-yl)-benzoicacid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylaminein THF and subsequent purification by washing the solution of theresidue in ethyl acetate with water, dilute sodium hydrogen carbonatesolution, water and sat. sodium chloride solution, drying over sodiumsulphate and eliminating the solvent i. vac.

Yield: 61%

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

C₂₀H₁₉ClN₄O₂ (382.85)

Mass spectrum: (M+H)⁺=383/385 (chlorine isotope)

EXAMPLE 123-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

(a) 3-chloro-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzonitrile

Prepared analogously to Example 1a from 3-chloro-4-fluoro-benzonitrileand 1-methyl-[1,4]diazepan in DIPEA with subsequent purification bychromatography on silica gel (eluting gradient: dichloromethane/ethanol98:2->94:6).

Yield: 71%

R_(f) value: 0.20 (silica gel; methylene chloride/ethanol=19:1)

C₁₃H₁₆ClN₃ (249.75)

Mass spectrum: (M+H)⁺=250/252 (chlorine isotope)

(b) 3-chloro-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid

Prepared analogously to Example 1b from3-chloro-4-(4-methyl-[1,4]diazepan-1-yl)-benzonitrile in 25% aqueouspotassium hydroxide solution.

Yield: 99%

C₁₃H₁₇ClN₂O₂*HCl (268.74/305.21)

Mass spectrum: (M+H)⁺=269/271 (chlorine isotope)

(c)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(4-methyl-[1,4]diazepan-1-yl)-benzoic acid,(S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THFwith subsequent purification by chromatography on silica gel (elutinggradient: petroleum ether/ethyl acetate 50:50->20:80).

Yield: 34%

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=9:1+1% ammoniasolution)

C₂₂H₂₅Cl₂N₅O (446.38)

Mass spectrum: (M+H)⁺=446/448/450 (chlorine isotope)

EXAMPLE 133-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(2-methyl-pyrrolidin-1-yl)-benzamide

(a) 3-chloro-4-(2-methyl-pyrrolidin-1-yl]-benzonitrile

5.90 g (37.9 mmol) 3-chloro-4-fluoro-benzonitrile are dissolved in 65 mlDMF under a nitrogen atmosphere and combined with 5.45 g (39.5 mmol)potassium carbonate and 4.2 ml (3.5 g, 39.5 mmol) 2-methyl-pyrrolidine.After stirring for 2.5 days at 90° C. the reaction mixture is pouredinto 400 ml of water and extracted with ethyl acetate. The combinedorganic phases are washed several times with dilute and sat. sodiumchloride solution, dried over magnesium sulphate and evaporated down i.vac. The residue remaining is further reacted without any morepurification.

Yield: 7.90 g (94%)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=9:1+0.5%ammonia solution)

C₁₂H₁₃ClN₂ (220.70)

Mass spectrum: (M+H)⁺=221/223 (chlorine isotope)

(b) 3-chloro-4-(2-methyl-pyrrolidin-1-yl)-benzoic acid

8.0 g (40 mmol) of the product obtained in Example 13a are stirred in amixture of 65 ml 10-molar sodium hydroxide solution and 65 ml of ethanolfor 2.75 hours at 90° C. Then the reaction mixture is poured into icewater, combined with conc. hydrochloric acid and volatile organicconstituents are evaporated down i. vac. The aqueous phase remaining isextracted with dichloromethane, combined with ice and adjusted to pH 4.5with semiconcentrated hydrochloric acid and 2-normal potassium hydrogensulphate solution. The resulting precipitate is stirred for another 10minutes, then filtered off, washed with water and dried at 55° C.

Yield: 8.30 g (87%)

R_(f) value: 0.55 (silica gel; petroleum ether/ethyl acetate=6:4+1%acetic acid) C₁₂H₁₄ClNO₂ (238.72)

Mass spectrum: (M+H)⁺=240/242 (chlorine isotope)

(c)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-4-(2-methyl-pyrrolidin-1-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(2-methyl-pyrrolidin-1-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and TEA in DMF,then precipitated by pouring into dilute sodium hydrogen carbonatesolution, filtering and washing with water. Then the product is dried at55° C.

Yield: 92%

R_(f) value: 0.66 (silica gel; dichloromethane/ethanol=9:1)

C₂₁H₂₂Cl₂N₄O (417.34)

Mass spectrum: (M−H)⁻=415/417/419 (chlorine isotope)

The following compounds were prepared analogously:

structural formula R_(f) value/R_(t) No. Name yield mass peak(s) value14

Σ: 11% (M + H)⁺ = 419/421/423 (chlorine isotope) 0.55 (silica gel,petroleum ether/ CH₃COOC₂H₅ 19:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-chloro-4-(morpholin-4-yl)-benzamide15

Σ: 19% (M + H)⁺ = 421/423 (chlorine isotope) 0.30 (silica gel, petroleumether/ CH₃COOC₂H₅ 1:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3,5-difluoro-4-(morpholin-4-yl)-benzamide16

Σ: 17% (M + H)⁺ = 483/485 (chlorine isotope) 3.46 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-4-(morpholin-4-yl)-benzamide17

Σ: 13% (M + H)⁺ = 465/467 (chlorine isotope) 3.21 min4-(azepan-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide18

Σ: 20% (M + H)⁺ = 431/433/435 (chlorine isotope 3.02 min4-(azepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide19

Σ: 49% (M + H)⁺ = 417/419/421 (chlorine isotope) 0.47 (silica gel,CH₂Cl₂/ isopropanol 19:1)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-1-yl)-benzamide20

Σ: 6.2% (M + H)⁺ = 433/435/437 (chlorine isotope) 2.61 min3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]oxazepan-4-yl)-benzamide37

Σ: 9.4% (M + H)⁺ = 411/413 (chlorine/ isotope) 0.53 (silica gel,CH₂Cl₂/CH₃OH 19:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-1-yl)-benzamide38

Σ: 20% (M − H)⁻ = 413/415/417 (chlorine isotope) 2.84 min3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,4-di-dehydro-piperidin-1-yl)-benzamide50

Σ: 1.2% (M + H)⁺ = 529/531/533 (chlorine isotope) 0.29 (silica gel,CH₂Cl₂/ CH₃OH 9:1) 2.38 min3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-[2-(4-methyl-piperazin-1-yl-methyl)-piperidin-1-yl)-benzamide

EXAMPLE 21N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide

(a) 4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzoic acid

1.00 g (3.63 mmol) 4-(morpholin-4-yl)-3-trifluoromethyl-benzoic acid(prepared by synthesis sequence analogously to Example 13a and 13b) issuspended in 40 ml of water and 150 mg (3.75 mmol) sodium hydroxide areadded. Then 1.73 g (10.92 mmol) potassium permanganate are added and themixture is stirred for 1.5 hours at 45° C. Then the reaction mixture iscooled in the ice bath and sodium thiosulphate is added until totaldecolorisation is obtained. After extraction 3 times with ethyl acetatethe combined organic phases are dried over sodium sulphate evaporateddown i. vac. After application of the residue to silica gel it ispurified by chromatography on silica gel (eluant:dichloromethane/methanol 95:5).

Yield: 340 mg (32%)

C₁₂H₁₀F₃NO₄ (289.21)

Mass spectrum: (M+H)⁺=290

(b) N′-(2-amino-4-chloro-phenyl)-N-Boc-(S)—O-methyl-serinamide andN′-(2-amino-5-chloro-phenyl)-N-Boc-(S)—O-methyl-serinamide

30.0 g (137 mmol) N-Boc-(S)—O-methyl-serine are dissolved together with21.9 g (154 mmol) 4-chloro-1,2-phenylenediamine in 658 ml THF, and 43.9ml (316 mmol) triethylamine and 103 ml (173 mmol) of a 50% solution ofPPA in ethyl acetate are added with stirring in the ice bath. After 15minutes stirring in the ice bath the mixture is heated to ambienttemperature, poured into water and the aqueous phase is extracted withethyl acetate. The combined organic phases are washed with sat. sodiumcarbonate solution and water, dried over sodium sulphate and evaporateddown i. vac. The residue is purified by chromatography on silica gel(eluting gradient: dichloromethane/methanol=30:1->9:1).

Yield: 33.47 g (72%) mixture of the two regioisomers

C₁₅H₂₂ClN₃O₄ (343.81)

Mass spectrum: (M−H)⁻=342/344 (chlorine isotope)

R_(f) value: 0.80 (silica gel; dichloromethane/methanol=9:1)

(c) (1R)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine

26.01 g (75.65 mmol) of the mixture obtained in Example 21b aredissolved in 1500 ml of toluene and 20.8 ml (364 mmol) acetic acid and10.0 g molecular sieve, 4 Å, are added. The reaction mixture is stirredfor 5 hours at 60° C. The reaction mixture is filtered, washed againwith ethyl acetate and the organic phase is washed with semisat. sodiumhydrogen carbonate solution, dried over sodium sulphate and evaporateddown i. vac. The residue is stirred with diethyl ether and the crystalsformed are suction filtered. The filtrate is evaporated down i. vac. andthe residue is purified by three lots of chromatography on silica gel(eluting gradient: dichloromethane/methanol 80:1->50:1).

Yield: 13.85 g (56%)

C₁₅H₂₀ClN₃O₃ (325.79)

Mass spectrum: (M+H)⁺=326/328 (chlorine isotope)

R_(f) value: 0.29 (silica gel; dichloromethane/methanol=30:1)

(d) (1R)-1-(5-chloro-1H-benzimidazol-1-yl)-2-methoxy-ethylamine

0.50 g (1.54 mmol)(1R)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine in 1.5ml dichloromethane are combined with 1.54 ml (20.0 mmol) TFA and stirredfor 2 h at ambient temperature. The mixture is then poured into sat.sodium hydrogen carbonate solution and after thorough mixing the aqueousphase is extracted with dichloromethane and ethyl acetate. The combinedorganic phases are dried over sodium sulphate and purified bychromatography on silica gel (eluant: dichloromethane/methanol=9:1+1%conc. ammonia solution).

Yield: 0.35 g (quant.)

C₁₀H₁₂ClN₃O (225.68)

Mass spectrum: (M−Hy=224/226 (chlorine isotope)

R_(f) value: 0.40 (silica gel, dichloromethane/methanol 9:1+1% conc.ammonia solution)

(e)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide

Prepared analogously to Example 1f from4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzoic acid,(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU andNMM in DMF, then precipitation by pouring into water, filtering anddrying i. vac.

Yield: 63%

R_(f) value: 0.57 (silica gel; dichloromethane/methanol=9:1)C₂₂H₂₀ClF₃N₄O₄ (496.88)

Mass spectrum: (M+H)⁺=497/499 (chlorine isotope)

The following compounds were prepared analogously:

structural formula No. Name Yield mass peaks(s) R_(f) value or R_(t) 25

Σ: 2.0% (M + H)⁺ = 475/477/479 (chlorine isotope) 2.57 min4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide26

Σ: 29% (M + H)⁺ = 509/511 (chlorine isotope) 2.65 min4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide 44

Σ: 8.5% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.47 (silica gel,CH₂Cl₂/CH₃OH 95:5) 2.37 min3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide 45

Σ: 2.2% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.45 (silica gel,CH₂Cl₂/CH₃OH 95:5) 2.41 min3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide 52

Σ: 7.2% (M − H)⁻ = 431/433/435 (chlorine isotope) 0.70 (silica gel,CH₃COOC₂H₅/ CH₃OH 9:1)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide 81

Σ: 2.9% (M + H)⁺ = 463/465/467 (chlorine isotope) 0.44 (silica gel,CH₃COOC₂H₅/ CH₃OH 95:5 + CH₃COOH)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide97

Σ: 1.0% (M − H)⁻ = 506/508/510 (bromine and chlorine isotope) 2.36 min3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide

EXAMPLE 22N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid (prepared by synthesissequence analogously to Example 30a, 2d and 21a),(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU andNMM in DMF, then pouring into water, extracting with ethyl acetate,drying over sodium sulphate, evaporation i. vac. and purifying bychromatography on silica gel (eluting gradient: ethylacetate/isopropanol/ethanol 9:1:0->9:0:1).

Yield: 99%

R_(f) value: 0.13 (silica gel; dichloromethane/isopropanol=19:1)

C₂₂H₂₃ClN₄O₄ (442.91)

Mass spectrum: (M+H)⁺=443/445 (chlorine isotope)

The following compounds were prepared analogously:

structural formula R_(f) value No. Name Yield mass peak(s) or R_(t) 23

76% (M + H)⁺ = 473/475 (chlorine isotope) 0.50 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 24

22% (M + H)⁺ = 429/431 (chlorine isotope) 0.22 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 49

quant. (M + H)⁺ = 412/414 (chlorine isotope) 0.60 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[1-(5-chloro-1H-indol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

EXAMPLE 27N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide

254 mg (1.15 mmol) 4-(morpholin-3-on-4-yl)-benzoic acid (prepared bysynthesis sequence analogously to Example 30a, 2d and 21a) are placed in5 ml DMF and 428 mg (1.0 mmol) PfTU and 514 μl (3.0 mmol) DIPEA areadded. After stirring at ambient temperature for 10 minutes 232 mg (1.0mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-hydrochlorideare added and the mixture is stirred for 16 hours at ambienttemperature. Then the reaction mixture is filtered through basicaluminium oxide and evaporated down i. vac. The residue is purified bychromatography on silica gel (eluting gradient: dichloromethane/methanol100:0->90:10), the corresponding fractions are evaporated down i. vac.,the residue is dissolved in acetonitrile/water and lyophilised.

Yield: 77%

C₂₀H₁₉ClN₄O₃ (398.85)

Mass spectrum: (M+H)⁺=399/401 (chlorine isotope)

The following compound is prepared analogously:

structural formula mass No. Name Yield peak(s) 28

80% (M + H)⁺ = 413/415 (chlorine isotope)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

EXAMPLE 29

N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

(a) 4-fluoro-3-methyl-benzoic acid chloride

14.00 g (90.8 mmol) 4-fluoro-3-methyl-benzoic acid are refluxed for 1hour together with 50 ml of thionyl chloride and then evaporated down i.vac. The residue is further reacted without any more purification.

Yield: 15.70 g (quantitative)

C₈H₈ClFO (172.59)

(b) 4-fluoro-3-methyl-benzamide

15.70 g (91.0 mmol) 4-fluoro-3-methyl-benzoic acid chloride dissolved in30 ml THF are added dropwise to 300 ml of conc. ammonia solution andthen stirred for 2 hours at ambient temperature. The precipitate formedis filtered off, washed with water and dried.

Yield: 10.00 g (72%)

C₈H₈FNO (153.16)

R_(f) value: 0.31 (aluminium oxide; dichloromethane/methanol=50:1)

(c) 4-fluoro-3-methyl-benzonitrile

10.00 g (65.29 mmol) 4-fluoro-3-methyl-benzoic acid amide are stirredtogether with 50 ml phosphorus oxychloride for 4 hours at 60° C. andthen evaporated down i. vac. The residue is poured into ice water, theresulting precipitate is filtered off and washed with water. After beingtaken up in ethyl acetate the organic phase is washed with sat.potassium carbonate solution, dried over sodium sulphate and evaporateddown completely i. vac.

Yield: 8.00 g (91%)

C₈H₆FN (135.14)

R_(f) value: 0.84 (silica gel; dichloromethane)

(d) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzonitrile

7.00 g (51.8 mmol) 4-fluoro-3-methyl-benzonitrile are heated to 110° C.together with 1-N-methyl-[1,4]diazepan for 1 week with stirring. Afterevaporation i. vac. the residue is separated on aluminium oxide (eluant:dichloromethane) and the corresponding fractions are again purified onsilica gel (eluting gradient: dichloromethane/methanol 100:1->9:1).

Yield: 1.70 g (14%)

C₁₄H₁₉N₃ (229.33)

Mass spectrum: (M+H)⁺=230

R_(f) value: 0.25 (silica gel; dichloromethane/methanol=9:1)

(e) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid

Prepared analogously to Example 1b from3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzonitrile with 25%potassium hydroxide solution by refluxing for 36 hours. Afterevaporation i. vac. the residue is separated on aluminium oxide (eluant:dichloromethane) and the corresponding fractions are again purified onsilica gel (eluting gradient: dichloromethane/methanol 100:1->9:1).

Yield: 14%

C₁₄H₁₉N₂O₂ (248.33)

Mass spectrum: (M+H)⁺=249

R_(f) value: 0.30 (RP-18; methanol/5/0 aqueous sodium chloridesolution=6:4)

(f) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride

Prepared analogously to Example 29a from3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid and thionylchloride.

Yield: quantitative

C₁₄H₁₉ClN₂O*HCl (266.77/303.23)

(g)N-[1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

489 mg (1.61 mmol) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoicacid chloride are placed together with 400 mg (3.96 mmol) TEA in 10 mlTHF at ambient temperature and a solution of 433 mg (1.61 mmol)(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl amine is added dropwisewith stirring. After 16 hours stirring at ambient temperature themixture is evaporated down i. vac., the residue is combined with waterand extracted with ethyl acetate. The combined organic phases are washedwith sat. sodium chloride solution, dried over sodium sulphate andevaporated down i. vac. The residue is purified by chromatography onaluminium oxide (eluant: dichloromethane/methanol 100:1). The fractionsevaporated down are treated with ethereal hydrochloric acid, after totalconcentration evaporated twice with ethyl acetate and diethyl ether anddried i. vac. at 70° C.

Yield: 120 mg (16%)

C₂₃H₂₈ClN₅O*HCl (462.43/425.96)

Mass spectrum: (M+H)⁺=426/428 (chlorine isotope)

R_(f) value: 0.47 (aluminium oxide; dichloromethane/methanol 19:1)

EXAMPLE 30N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide

(a) methyl 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoate

4.00 g (17.5 mmol) 4-bromo-3-methyl-benzoate methyl are suspendedtogether with 3.92 g (21.0 mmol) N-Boc-piperazine, 39.2 mg (175 μmol)palladium(II)acetate, 50.7 mg (175 μmol)tri-tert.-butyl-phosphonium-tetrafluoroborate and 11.12 g (52.4 mmol)potassium phosphate in 35 ml of toluene and under an argon atmosphereheated to 150° C. for 10 minutes in a microwave oven. Then the reactionmixture is poured into water, stirred vigorously and extracted 3 timeswith ethyl acetate. The combined organic phases are dried over sodiumsulphate, applied to silica gel and purified by chromatography on silicagel (eluant: dichloromethane/methanol 80:1).

Yield: 1.42 g (24%)

C₁₈H₂₆N₂O₄ (334.42)

Mass spectrum: (M+H)⁺=335

R_(f) value: 0.52 (silica gel; dichloromethane/methanol=50:1)

(b) 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoic acid

1.42 g (4.24 mmol) of methyl 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoateare dissolved in 7 ml THF and 9.25 ml of water and 893 mg (21.3 mmol)lithium hydroxide-monohydrate are added. After stirring for 16 hours atambient temperature the mixture is heated to 45° C. for 2 hours. Thenanother 893 mg (21.3 mmol) lithium hydroxide monohydrate are added andthe mixture is stirred for 4 days at ambient temperature. Then it isneutralised with 1-molar hydrochloric acid and the reaction mixture isextracted with ethyl acetate. The combined organic phases are dried oversodium sulphate and evaporated down completely i. vac.

Yield: 1.29 g (95%)

C₁₇H₂₄N₂O₄ (320.39)

Mass spectrum: (M+H)⁺=321

R_(f) value: 0.29 (silica gel; dichloromethane/methanol=15:1)

(c)4-(N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide

Prepared analogously to Example 1f from4-(N-Boc-piperazin-1-yl)-3-methyl-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF,then stirring into conc. sodium hydrogen carbonate solution, extractionwith ethyl acetate, drying over sodium sulphate, evaporation i. vac. andpurification of the residue by chromatography on silica gel (elutinggradient: dichloromethane/methanol 50:1->15:1).

Yield: 85%

R_(f) value: 0.15 (silica gel; dichloromethane/methanol=30:1)

C₂₆H₃₂ClN₅O₃ (498.03)

Mass spectrum: (M+H)⁺=498/500 (chlorine isotope)

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide

Prepared analogously to Example 1g from4-(N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamideand TFA in dichloromethane.

Yield: quantitative

C₂₁H₂₄ClN₅O (397.91)

Mass spectrum: (M+H)⁺=398/400 (chlorine isotope)

R_(f) value: 0.14 (silica gel; dichloromethane/methanol=9:1)

The following compound is prepared analogously:

structural formula R_(f) value No. Name Yield mass peak(s) or R_(t) 65

Σ: 5.9% (M + H)⁺ = 428/430 (chlorine isotope) 0.11 (silica gel, CH₂Cl₂/CH₃OH 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide

EXAMPLE 31N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide

(a) methyl 4-(N-Boc-piperazin-2-on-1-yl)-3-methyl-benzoate

758 mg (3.31 mmol) methyl 4-bromo-3-methyl-benzoate are suspendedtogether with 796 mg (21.0 mmol) 4-N-Boc-piperazin-2-one, 31.8 mg (167μmol) copper(I)iodide, 35.1 μl (330 μmol) N,N′-dimethyl-ethylenediamineand 0.92 g (6.62 mmol) potassium carbonate in 6.6 ml of toluene andunder an argon atmosphere heated to 140° C. in a microwave oven withstirring for 1.5 hours. Then the reaction mixture is poured into water,stirred vigorously and extracted 3 times with ethyl acetate. Thecombined organic phases are dried over sodium sulphate, applied tosilica gel and purified by chromatography on silica gel (eluant:dichloromethane/methanol 50:1).

Yield: 679 mg (59%)

C₁₈H₂₄N₂O₅ (348.40)

Mass spectrum: (M+H)⁺=349

R_(f) value: 0.25 (silica gel; dichloromethane/methanol=50:1)

(b) 4-(N-Boc-piperazin-2-on-1-yl)-3-methyl-benzoic acid

775 mg (2.22 mmol) methyl4-(N-Boc-piperazin-2-on-1-yl)-3-methyl-benzoate are dissolved in 3.7 mlTHF and 4.9 ml of water as well as 468 mg (11.2 mmol) lithiumhydroxide-monohydrate are added. After stirring for 16 hours at ambienttemperature the mixture is neutralised with 1-molar hydrochloric acidand the reaction mixture is extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and evaporated downcompletely i. vac.

Yield: 664 mg (89%)

C₁₇H₂₂N₂O₅ (334.38)

Mass spectrum: (M+H)⁺=335

R_(f) value: 0.31 (silica gel; dichloromethane/methanol=15:1)

(c)4-(N-Boc-piperazin-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide

Prepared analogously to Example 1f from4-(N-Boc-piperazin-1-yl)-3-methyl-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF,then stirring into conc. sodium hydrogen carbonate solution, extractionwith ethyl acetate, drying over sodium sulphate, evaporation i. vac. andpurification of the residue by chromatography on silica gel (eluant:dichloromethane/methanol 30:1).

Yield: 71%

R_(f) value: 0.30 (silica gel; dichloromethane/methanol=15:1)

C₂₆H₃₀ClN₅O₄ (512.01)

Mass spectrum: (M+H)⁺=512/514 (chlorine isotope)

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide

Prepared analogously to Example 1g from4-(N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamideand TFA in dichloromethane.

Yield: 36%

C₂₁H₂₂ClN₅O₂ (411.90)

Mass spectrum: (M+H)⁺=412/414 (chlorine isotope)

R_(f) value: 0.42 (silica gel; dichloromethane/methanol=9:1)

The following compounds were prepared analogously:

structural formula R_(f) value No. Name Yield mass peak(s) or R_(t) 66

Σ: 17% (M + H)⁺ = 442/444 (chlorine isotope) 0.18 (silica gel, CH₂Cl₂/CH₃OH 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide98

Σ: 0.11% (M + H)⁺ = 426/428 (chlorine isotope)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(7-oxo-[1,4]diazepan-1-yl)-benzamide

EXAMPLE 32N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide

(a) methyl 3-methyl-4-(piperidin-2-on-1-yl)-benzoate

Prepared analogously to Example 31a from methyl4-bromo-3-methyl-benzoate and piperidin-2-one in the presence ofcopper(I)iodide, N,N′-dimethyl-ethylenediamine and potassium carbonatein toluene and dioxane under an argon atmosphere.

Yield: 34%

C₁₄H₁₇NO₃ (247.30)

Mass spectrum: (M+H)⁺=248

R_(f) value: 0.21 (silica gel; petroleum ether/ethyl acetate=1:1)

(b) 3-methyl-4-(piperidin-2-on-1-yl)-benzoic acid

Prepared analogously to Example 2d from methyl3-methyl-4-(piperidin-2-on-1-yl)-benzoate and 1-molar sodium hydroxidesolution in methanol.

Yield: 83%

C₁₃H₁₅NO₃ (233.27)

Mass spectrum: (M+H)⁺=234

R_(f) value: 0.51 (silica gel; ethyl acetate/ethanol=9:1+1% conc.ammonia solution)

(c)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-4-(piperidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(piperidin-1-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF,then stirring into ice water, combining with ammonia solution,filtering, taking up in dichloromethane, evaporation i. vac. andpurification of the residue by chromatography on silica gel (elutinggradient: ethyl acetate/(methanol/conc. ammonia solution 19:1)1:0->9:1).

Yield: 32%

R_(f) value: 0.30 (silica gel; ethyl acetate/ethanol=9:1+1% acetic acid)

C₂₂H₂₃ClN₄O₂ (410.91)

Mass spectrum: (M+H)⁺=411/413 (chlorine isotope)

The following compounds were prepared analogously:

structural formula No. Name Yield mass peak(s) R_(f) value or R_(t) 55

Σ: 4.5% (M + H)⁺ = 429/431 (chlorine isotope) 0.40 (silica gel,CH₃COOC₂H₅/ C₂H₅OH 19:1 + 1% NH₃)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide56

Σ: 16% (M + H)⁺ = 441/443 (chlorine isotope) 0.30 (silica gel,CH₃COOC₂H₅/ C₂H₅OH 9:1 + 1% NH₃)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide80

Σ: 8.0% (M + H)⁺ = 459/461 (chlorine isotope) 0.60 (silica gel,CH₃COOC₂H₅/ C₂H₅OH 9:1 + 1% NH₃)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide

EXAMPLE 33N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(N-methyl-piperazin-1-yl)-3-trifluoromethyl-benzamide

170 mg (0.24 mmol)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamideare suspended in 2 ml 1,2-dichloroethane and under a nitrogen atmospherecombined with 20 mg (0.67 mmol) paraformaldehyde and 76 mg (0.36 mmol)sodium triacetoxyborohydride. After the addition of 5 ml THF thereaction mixture is stirred for 6 hours at ambient temperature, then 100mg (3.33 mmol) of paraformaldehyde and 100 mg (0.47 mmol) sodiumtriacetoxyborohydride are added and the mixture is stirred for a further22 hours at ambient temperature. Then it is combined with sat. sodiumhydrogen carbonate solution and extracted with ethyl acetate. Thecombined organic phases are dried over magnesium sulphate, evaporateddown i. vac. and purified by chromatography on silica gel (elutinggradient: dichloromethane/(methanol/conc. ammonia solution 19:1)100:0->92:8).

Yield: 70 mg (59%)

C₂₃H₂₅ClF₃N₅O₂ (495.94)

Mass spectrum: (M+H)⁺=496/498 (chlorine isotope)

R_(f) value: 0.25 (silica gel; dichloromethane/methanol=9:1+1% conc.ammonia solution)

EXAMPLE 34N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

150 mg (0.32 mmol)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-prop-1-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamideare dissolved in a mixture of 10 ml dichloromethane and 1 ml acetic acidat −15° C. and combined with 204 mg (0.89 mmol) 3-chloroperbenzoic acid.The mixture is then stirred for 30 minutes at −15 to −10° C., heated toambient temperature and stirred for a further 16 hours. Then thereaction mixture is washed twice with 5% sodium hydrogen carbonatesolution, dried over sodium sulphate, evaporated down i. vac. andpurified by chromatography on silica gel (eluant:dichloromethane/ethanol 95:5).

Yield: 80 mg (50%)

C₂₃H₂₅ClN₄O₅S (505.00)

Mass spectrum: (M+H)⁺=505/507 (chlorine isotope)

R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 35

N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(pyrrolidin-2-on-1-yl)-benzamide

Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoicacid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine,PfTU and TEA in DMSO at ambient temperature and subsequent Boc cleavingwith TFA analogously to Example 1g.

HPLC-MS results:

retention time: 3.69 min

C₂₂H₂₃ClN₄O₂S (442.97)

Mass spectrum: (M+H)⁺=443/445 (chlorine isotope)

The following compound is prepared analogously:

structural formula mass peak(s) retention time No. Name 36

(M + H)⁺ = 445/447 (chlorine isotope) 3.80 minN-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-4-(pyrrolidin-2-on-1-yl)-benzamide

EXAMPLE 39N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

(a) methyl 4-isocyanato-3-methyl-benzoate

1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250ml dioxane combined with 1.3 ml (10.7 mmol)trichloromethyl-chloroformate and refluxed for 5.5 hours with stirring.Then the mixture is evaporated down i. vac.

and the residue is further reacted without any more purification.

Yield: 1.74 g (quantitative)

C₁₀H₉NO₃ (191.19)

(b) methyl 4-(N-[4-chlorobutoxycarbonyl]amino)-3-methyl-benzoate

1.74 g (9.08 mmol) 4 methyl-isocyanato-3-methyl-benzoate dissolved in100 ml of toluene are combined with 1.07 ml (9.11 mmol) 85% m4-chloro-butan-1-ol. The mixture is refluxed for 17 hours with stirring.After evaporation i. vac. the residue is purified by chromatography onsilica gel (eluting gradient: petroleum ether/ethyl acetate 17:3->17:4).

Yield: 1.19 g (44%)

C₁₄H₁₈ClNO₄ (299.76)

Mass spectrum: (M−H)⁻=298/300 (chlorine isotope)

R_(f) value: 0.45 (silica gel; petroleum ether/ethyl acetate=80:20)

(c) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoate

300 mg (1.00 mmol) methyl4-(N-[4-chlorobutoxycarbonyl]-amino)-3-methyl-benzoate are dissolved in10 ml DMF combined with 168 mg (1.50 mmol) potassium-tert.-butoxide andstirred for 3 hours at 60° C. The reaction mixture is mixed with waterand extracted 3 times with ethyl acetate. The combined organic phasesare dried over sodium sulphate and evaporated down i. vac. Then theresidue is purified by chromatography on silica gel (eluant: petroleumether/ethyl acetate 3:2).

Yield: 160 mg (61%)

R_(f) value: 0.26 (silica gel; petroleum ether/ethyl acetate 3:2)

C₁₄H₁₇NO₄ (263.30)

Mass spectrum: (M+H)⁺=264

(d) 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid

150 mg (0.57 mmol) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoateare suspended in 1 ml of ethanol and combined with 0.26 ml (0.87 mmol)8% aqueous lithium hydroxide solution. The mixture is stirred for 3hours at ambient temperature and then evaporated down i. vac. Theaqueous residue is extracted twice with ethyl acetate, then acidifiedand extracted twice more with ethyl acetate. The combined organic phasesare dried over sodium sulphate and evaporated down i. vac.

Yield: 122 mg (86%)

C₁₃H₁₅NO₄ (249.27)

Mass spectrum: (M+H)⁺=250

R_(f) value: 0.14 (silica gel; dichloromethane/methanol=95:5)

(e)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF,then acidifying with TFA and purification of the residue bychromatography (preparative HPLC).

Yield: 54%

C₂₂H₂₃ClN₄O₃*2 CF₃COOH (654.96/426.90)

Mass spectrum: (M+H)⁺=427/429 (chlorine isotope)

R_(t): 2.42 min

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(t) No. Name 43

Σ: 12% (M − H)⁻ = 455/457 (chlorine isotope) 2.43 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide 51

Σ: 2.6% (M − H)⁻ = 397/399 (chlorine isotope) 3.70 minN-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(oxazolidin-2-on-3-yl)-benzamide 57

Σ: 3.4% (M + H)⁺ = 413/415 (chlorine isotope) 3.63 minN-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide 58

Σ: 2.7% (M + H)⁺ = 443/445 (chlorine isotope) 3.66 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide 68

Σ: 0.32% (M + H)⁺ = 511/513 (chlorine isotope) 4.21 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide

EXAMPLE 41N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide

(a) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate

1.00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 mldioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogenatmosphere and 36.6 mg (40 μmol)tris-(dibenzylideneacetone)-dipalladium(0), 67.1 mg (116 μmol) xantphosand 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogenatmosphere and with stirring, the reaction mixture is heated to 95° C.for 16 hours. Then it is filtered, the solution is evaporated down i.vac. and evaporated with ether. The residue is further reacted withoutany more purification. Yield: 1.31 g (quantitative)

C₁₂H₁₂N₂O₆ (280.24)

Mass spectrum: (M+H)⁺=281

R_(f) value: 0.47 (Reversed phase 8; methanol/5% sodium chloridesolution=6:4)

(b) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid

400 mg (1.43 mmol) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate aredissolved in 15 ml of methanol and combined with 4.5 ml (4.5 mmol)1-molar lithium hydroxide solution. The mixture is stirred for 2 hoursat ambient temperature. Then it is evaporated down i. vac., the residueis diluted with water, cooled in the ice bath and acidified with 2-molarhydrochloric acid. After 10 minutes cooling in the ice bath theprecipitate formed is filtered off, washed with water until neutral anddried at 50° C. in the drying cupboard.

Yield: 290 mg (72%)

C₁₁H₁₂N₂O₇ (284.23)

Mass spectrum: M⁺=284

R_(f) value: 0.59 (Reversed phase 8; methanol/5/0 sodium chloridesolution=6:4)

(c) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid-chloride

290 mg (1.02 mmol) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acidin 100 ml dichloromethane are combined with 0.186 ml (2.55 mmol) thionylchloride and 2 drops of DMF and refluxed for one day. After evaporationof the solution i. vac. it is evaporated with toluene and the residue isfurther reacted without any more purification.

Yield: 290 mg (quant.)

C₁₁H₉ClN₂O₅ (284.66)

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide

237 mg (0.93 mmol) of(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine aredissolved with 0.257 ml TEA in 10 ml THF and a solution of 290 mg (1.02mmol) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid chloride in 10 ml THFis added dropwise. The reaction mixture is stirred for 16 hours atambient temperature and then evaporated down i. vac. The residue ispurified by chromatography on silica gel (eluting gradient:dichloromethane/ethanol 100:0->95:5).

Yield: 34%

C₂₂H₂₂ClN₅O₅S (503.97)

Mass spectrum: (M−H)⁻=502/504 (chlorine isotope)

R_(f) value: 0.46 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 423-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide

(a) 4-(3-Boc-amino-propyl-amino)-3-chloro-benzonitrile

3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol)3-chloro-4-fluoro-benzonitrile the mixture is stirred for 3.5 hours atambient temperature under a nitrogen atmosphere, heated to 105° C. for20 minutes and extracted with ethyl acetate. The combined organic phasesare washed with water and sat. sodium chloride solution, dried overmagnesium sulphate and evaporated down i. vac. The residue is furtherreacted without any more purification.

Yield: 5.50 g (89%)

C₁₅H₂₀N₃O₂ (309.80)

Mass spectrum: (M+H)⁺=310/312 (chlorine isotope)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=2:1)

(b) 4-(3-amino-propylamino)-3-chloro-benzonitrile

4.50 g (14.5 mmol) 4-(3-Boc-amino-propylamino)-3-chloro-benzonitrile aredissolved in 50 ml dioxane and combined with 200 ml 6-molar hydrochloricacid. The mixture is stirred for 2 hours at ambient temperature, thenwashed with ether and the aqueous phase is poured into 125 ml ice-cooledconc. ammonia solution. Then the mixture is extracted with ethylacetate, the combined organic phases are washed with water and sat.sodium chloride solution, dried over magnesium sulphate and evaporateddown i. vac. The residue is further reacted without any morepurification.

Yield: 1.40 g (46%)

C₁₀H₁₂ClN₃ (209.68)

Mass spectrum: (M+H)⁺=210/212 (chlorine isotope)

R_(f) value: 0.30 (silica gel; dichloromethane/methanol=9:1+1% conc.ammonia solution)

(c) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzonitrile

A solution of 349 mg (2.15 mmol) N,N′-carbonyl-diimidazole in 3 ml NMPis combined with 450 mg (2.15 mmol)4-(3-amino-propylamino)-3-chloro-benzonitrile at ambient temperaturewith stirring and once fully dissolved heated for one hour to 145° C.and for 1.5 hours to 155° C. The reaction mixture is washed with waterand extracted with ethyl acetate. The combined organic phases are washedwith water and sat. sodium chloride solution, dried over magnesiumsulphate and evaporated down i. vac. Then the residue is purified bychromatography on silica gel (eluting gradient: ethylacetate/(methanol/conc. ammonia solution 19:1)=100:0->95:5).

Yield: 260 mg (51%)

R_(f) value: 0.40 (silica gel; ethyl acetate/ethanol 9:1+1% conc.ammonia solution)

C₁₁H₁₀ClN₃O (235.68)

Mass spectrum: (M+H)⁺=236/238 (chlorine isotope)

(d) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid

350 mg (1.49 mmol)3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzonitrile are suspendedin 5 ml of ethanol and combined with 2.0 ml of 10-molar aqueous sodiumhydroxide solution. The mixture is stirred for one hour at 100° C. andthen evaporated down i. vac. The aqueous residue is combined with ice,acidified with acetic acid and extracted with ethyl acetate. Thecombined organic phases are washed with water and sat. sodium chloridesolution, dried over magnesium sulphate and evaporated down i. vac. Theaqueous phase is acidified with 6-molar hydrochloric acid, extracted 5times with ethyl acetate, the combined organic phases are washed withsat. sodium chloride solution, dried over magnesium sulphate andevaporated down i. vac.

Yield: 340 mg (90%)

C₁₁H₁₁ClN₂O₃ (254.68)

Mass spectrum: (M+H)⁺=255/257 (chlorine isotope)

R_(f) value: 0.35 (silica gel; dichloromethane/methanol=9:1+1% aceticacid)

(e)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF,then pouring into ice water, adding conc. ammonia solution, filtering,washing with water and purifying by chromatography on silica gel(eluting gradient ethyl acetate/(methanol/conc. ammonia solution19:1)=98:2->90:10) with subsequent filtration through activatedcharcoal, trituration with ether and drying in the drying pistol at 70°C.

Yield: 32%

C₂₀H₁₉Cl₂N₅O₂ (432.31)

Mass spectrum: (M+H)⁺=432/434/436 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/methanol=9:1+1% aceticacid)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 114

Σ: 5.4% (M + H)⁺ = 462/464/466 (chlorine isotope) 0.52 (ethyl acetate/ethanol = 8:2)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide

EXAMPLE 463-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide

(a) methyl 3-chloro-4-(5-chloro-pentanoyl-amino)-benzoate

A solution of 696 μl (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl4-amino-3-chloro-benzoate in 20 ml THF with 1 ml TEA with stirring inthe ice bath. After stirring for 16 hours at ambient temperature, for 3hours at 50° C. and for 3 hours at reflux temperature the mixture ispoured into water and extracted with ethyl acetate. After the organicphases have been dried over sodium sulphate the mixture is evaporateddown i. vac. and the residue remaining is purified by chromatography onsilica gel (eluant: petroleum ether/ethyl acetate 85:15).

Yield: 300 mg (14.6%) 80% product

C₁₃H₁₅Cl₂NO₃ (304.18)

Mass spectrum: (M+H)⁺=304/306/308 (chlorine isotope)

R_(t) value: 3.29 min

(b) methyl 3-chloro-4-(piperidin-2-on-1-yl)-benzoate

300 mg (0.79 mmol) of the product obtained in Example 46a is dissolvedin 10 ml DMF and combined with 180 mg (1.60 mmol)potassium-tert.-butoxide and heated to 60° C. for 3 hours. Then thereaction mixture is poured into water and extracted with ethyl acetate.The combined organic phases are dried over sodium sulphate, evaporateddown i. vac. and the residue obtained is purified by chromatography onsilica gel (eluant: dichloromethane/isopropanol 98:2).

Yield: 159 mg (75%)

C₁₃H₁₄ClNO₃ (267.71)

Mass spectrum: (M+H)⁺=268/270 (chlorine isotope)

R_(f) value: 0.18 (silica gel; dichloromethane/isopropanol=49:1)

(c) 3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid

Prepared analogously to Example 39d from methyl3-chloro-4-(piperidin-2-on-1-yl)-benzoate and 8% lithium hydroxidesolution in ethanol.

Yield: 36%

C₁₂H₁₂ClNO₃ (247.30)

Mass spectrum: (M+H)⁺=252/254 (chlorine isotope)

R_(f) value: 0.27 (silica gel; dichloromethane/ethanol=9:1)

(d)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine in DMF andsubsequent purification by chromatography on silica gel (elutinggradient: ethyl acetate/ethanol 95:5->90:10).

Yield: 70%

C₂₂H₂₂Cl₂N₄O₃ (461.35)

Mass spectrum: (M−Hy=459/461/463 (chlorine isotope)

R_(f) value: 0.19 (silica gel; dichloromethane/ethanol=19:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 59

Σ: 1.3% (M + H)⁺ = 495/497 (chlorine isotope) 2.51 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethyl-benzamide

EXAMPLE 47N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-bromo-phenyl)-N-Boc-(S)-serinamide andN′-(2-amino-5-bromo-phenyl)-N-Boc-(S)-serinamide

5.49 g (26.7 mmol) (S)—N-Boc-serine are dissolved with 5.00 g (26.7mmol) 4-bromo-1,2-phenylenediamine in 125 ml THF and a solution of 5.52g (26.7 mmol) N,N′-dicyclohexylcarbodiimide in 20 ml THF is addeddropwise while cooling with ice. The reaction mixture is stirred for 16hours at ambient temperature. After evaporation i. vac. the residue ispurified by chromatography on silica gel (eluant:dichloromethane/methanol 98:2).

Yield: 4.76 g (48%) mixture of the two regioisomers

C₁₄H₂₀BrN₃O₄ (374.24)

Mass spectrum: (M+H)⁺=374/376 (bromine isotope)

(b) (1R)—N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine

3.00 g (8.02 mmol) of the mixture obtained in 47a are dissolved in 30 mlacetic acid and stirred for 2 hours at 50° C. The reaction mixture isadded dropwise to a 10% sodium hydroxide solution and extracted 3 timeswith ethyl acetate. The combined organic phases are dried over magnesiumsulphate and evaporated down i. vac. and the residue is recrystallisedfrom methanol.

Yield: 1.96 g (69%)

C₁₄H₁₈BrN₃O₃ (356.22)

R_(f) value: 0.59 (silica gel; petroleum ether/ethyl acetate=1:1)

(c) (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine

2.00 g (5.62 mmol)(1R)—N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine in 40ml of ethyl acetate are combined with 8.0 ml 4-molar hydrochloric acidin dioxane while cooling in the ice bath and stirred for 16 hours atambient temperature. The reaction mixture is evaporated down and theresulting precipitate is filtered off.

Yield: 1.11 g (67%)

C₉H₁₀BrN₃O*HCl (292.57/256.10)

Mass spectrum: (M+H)⁺=256/258 (bromine isotope)

(d)N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid,(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMMin DMF with subsequent purification by preparative HPLC.

Yield: 52%

C₂₁H₂₁BrN₄O₄*CF₃COOH (587.35/473.32)

Mass spectrum: (M+H)⁺=473/475 (bromine isotope)

R_(f) value: 0.33 (silica gel; dichloromethane/methanol=19:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 53

Σ: 6.6% (M + H)⁺ = 457/459 (chlorine isotope) 0.48 (silica gel,CH₂Cl₂/C₂H₅OH 9:1)N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 62

Σ: 34% (M − H)⁻ = 441/443 (chlorine isotope) 0.40 (aluminium oxide,CH₂Cl₂/C₂H₅OH 19:1)4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-6-fluoro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide 67

Σ: 38% (M + H)⁺ = 441/443 (chlorine isotope) 0.50 (silica gel,CH₂Cl₂/C₂H₅OH 9:1)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 78

Σ: 38% (M + H)⁺ = 481/483 (chlorine isotope) 0.51 (silica gel,CH₂Cl₂/C₂H₅OH 9:1)N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 79

Σ: 10.6% (M + H)⁺ = 459/461 (chlorine isotope) 0.50 (silica gel,CH₂Cl₂/C₂H₅OH 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 99

Σ: 18% (M + H)⁺ = 481/483 (chlorine isotope) 2.43 minN-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 101

Σ: 2.9% (M + H)⁺ = 487/489 (bromine isotope) 2.31 minN-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

EXAMPLE 48N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzamide

(a) methyl 4-(3-chloro-propyl-sulphonyl-amino)-3-methyl-benzoate

100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml ofpyridine are combined with 82 μl (0.67 mmol) 3-chloropropanesulphonicacid chloride and stirred for 16 hours at ambient temperature. Thereaction solution is combined with water and ethyl acetate and then theaqueous phase is again extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and evaporated down i.vac. The residue is further reacted without any more purification.

Yield: 170 mg (92%)

C₁₂H₁₆ClNO₄S (305.78)

Mass spectrum: (M+H)⁺=306/308 (chlorine isotope)

R_(f) value: 0.10 (silica gel; petroleum ether/ethyl acetate=8:2)

(b) methyl 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoate

370 mg (0.85 mmol) 70% methyl4-(3-chloropropane-sulphonylamino)-3-methyl-benzoate dissolved in 26 mlDMF are combined with 275 mg (2.45 mmol) potassium-tert.-butoxide andstirred for 16 hours at ambient temperature. The reaction mixture iscombined with water and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate, evaporated down i. vac.and the residue is purified by chromatography on silica gel (eluant:dichloromethane/isopropanol 98:2).

Yield: 177 mg (47%)

C₁₂H₁₅NO₄S (269.32)

Mass spectrum: (M+H)⁺=270

R_(f) value: 0.10 (silica gel; petroleum ether/ethyl acetate=7:3)

(c) 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoic acid

170 mg (0.63 mmol) methyl4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoate are stirred in 2 mlof ethanol at ambient temperature for 3 hours with 0.6 ml of 2-molarsodium hydroxide solution. Then the reaction solution is evaporated downi. vac., combined with water and 0.6 ml 2-molar hydrochloric acid andextracted with ethyl acetate. The combined organic phases are dried oversodium sulphate, evaporated down i. vac. and the residue is furtherreacted without any more purification.

Yield: 148 mg (92%)

C₁₁H₁₃NO₄S (255.30)

Mass spectrum: (M−H)⁻=254

retention time: 2.23 min

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMFwith subsequent extraction with ethyl acetate, drying over magnesiumsulphate, activated charcoal and silica gel followed by purification onsilica gel (eluant: dichloromethane/isopropanol 95:5).

Yield: 37%

C₂₀H₂₁ClN₄O₃S (432.93)

Mass spectrum: (M+H)⁺=433/435 (chlorine isotope)

R_(f) value: 0.32 (silica gel; dichloromethane/isopropanol=19:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 60

Σ: 18% (M + H)⁺ = 477/479 (chlorine isotope) 2.46 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide 71

Σ: 20% (M + H)⁺ = 478/480 (chlorine isotope) 2.58 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide 72

Σ: 19% (M + H)⁺ = 448/450 (chlorine isotope) 2.41 minN-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide 100

Σ: 2.5% (M + H)⁺ = 507/509 (bromine isotope) 2.38 minN-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide

EXAMPLE 543-amino-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-benzamide

65 mg (0.13 mmol)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamidedissolved in 2 ml of ethyl acetate are combined with 143 mg (0.63 mmol)tin(II)chloride-dihydrate and 130 mg (1.55 mmol) sodium hydrogencarbonate and refluxed for 2 hours. The reaction solution is combinedwith ice water, stirred for 10 minutes and then the precipitate formedis filtered off. After drying for 3 days the residue is purified bychromatography on silica gel (eluting gradient: dichloromethane/ethanol100:0->91:9).

Yield: 5 mg (8.2%)

C₂₂H₂₄ClN₅O₃S (473.99)

Mass spectrum: (M+H)⁺=474/476 (chlorine isotope)

R_(f) value: 0.48 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 61N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-didehydro-azepan-2-on-1-yl)-benzamide

(a) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate

Prepared analogously to Example 46a from methyl4-amino-3-methyl-benzoate and 4-pentene-1-acid-chloride in THF with TEA.

Yield: 46%

C₁₄H₁₇NO₃ (247.30)

Mass spectrum: (M+H)⁺=248

R_(t) value: 2.88 min

(b) methyl 4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate

1.00 g (4.04 mmol) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoatedissolved in 5 ml DMF are combined with 500 mg (4.37 mmol)potassium-tert.-butoxide and at 40° C. 350 μl (489 mg, 4.04 mmol)allylbromide are slowly added with stirring. Then the mixture is heatedto 70° C. for 3 hours. Then the reaction mixture is poured into waterand extracted with ethyl acetate. The combined organic phases are driedover sodium sulphate, evaporated down i. vac., the residue is applied tosilica gel and purified by chromatography on silica gel (eluant:petroleum ether/ethyl acetate 9:1).

Yield: 58%

C₁₇H₂₁NO₃ (287.36)

Mass spectrum: (M+H)⁺=288

R_(f) value: 0.46 (petroleum ether/ethyl acetate=9:1)

(c) methyl 4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoate

150 mg (0.52 mmol) methyl4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate are dissolved in 110ml degassed dichloromethane and rinsed for 30 minutes with argon. Then88 mg (104 μmol)benzylidene-[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium(2nd generation Grubbs Catalyst) are added and the mixture is refluxedfor 4.5 hours. Then it is evaporated down i. vac., the residue isapplied to silica gel and purified by chromatography on silica gel(eluant: petroleum ether/ethyl acetate 3:2).

Yield: 83 mg (61%)

R_(f) value: 0.22 (silica gel, petroleum ether/ethyl acetate 3:2)

C₁₅H₁₇NO₃ (259.31)

Mass spectrum: (M+H)⁺=260

(d) 4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoic acid

Prepared analogously to Example 39d from methyl4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoate and 8% lithiumhydroxide solution in ethanol. Yield: 51%

R_(f) value: 0.05 (silica gel; dichloromethane/methanol=19:1)

C₁₄H₁₅NO₃ (245.28)

Mass spectrum: (M+H)⁺=246

(e)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoic acid, TBTU, NMM and(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine in DMF and subsequentpurification by preparative HPLC.

Yield: 32%

R_(f) value: 0.44 (silica gel; dichloromethane/methanol=19:1)

C₂₃H₂₃ClN₄O₂*CF₃COOH (536.94/422.91)

Mass spectrum: (M+H)⁺=423/425 (chlorine isotope)

EXAMPLE 63N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,3-dioxo-thiomorpholin-4-yl)-3-methyl-benzamide

204 mg (0.48 mmol)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamideare dissolved in a mixture of 12 ml dichloromethane and 1.2 ml aceticacid at −15° C. and combined with 110 mg (0.48 mmol) 3-chloroperbenzoicacid. The mixture is then stirred for one hour at −15 to −10° C., heatedto ambient temperature and stirred for a further 3 hours. Then thereaction mixture is combined with semi-concentrated sodium hydrogencarbonate solution and extracted with a solvent mixturedichloromethane/methanol 19:1. The combined organic phases are washedwith water, dried over magnesium sulphate, evaporated down i. vac. andpurified by chromatography on silica gel (eluting gradient: ethylacetate/(ethanol/conc. ammonia solution 19:1)=1:0->4:1).

Yield: 100 mg (47%)

C₂₁H₂₁ClN₄O₃S (444.94)

Mass spectrum: (M+H)⁺=445/447 (chlorine isotope)

R_(f) value: 0.15 (silica gel; ethyl acetate/ethanol=4:1+1% conc.ammonia solution)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value No. Name 64

Σ: 14% (M + H)⁺ = 461/463 (chlorine isotope) 0.70 (silica gel,CH₃COOC₂H₅/ C₂H₅OH 4:1 + 1% conc. ammonia solution)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(1,1,3-trioxo-thiomorpholin-4-yl)-benzamide

EXAMPLE 69N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide

(a) methyl 4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate

Prepared analogously to Example 6a from methyl4-amino-3-methoxy-benzoate and 5-chloro-pentanoic acid chloride in THFwith TEA.

Yield: 99%

C₁₄H₁₈ClNO₄ (299.76)

Mass spectrum: (M+H)⁺=300/302 (chlorine isotope)

R_(t) value: 3.14 min

(b) methyl 3-methoxy-4-(piperidin-2-on-1-yl)-benzoate

2.25 g (7.51 mmol) methyl4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate dissolved in 60 ml DMFare combined with 1.26 g (11.2 mmol) potassium-tert.-butoxide andstirred for 2.5 hours at 60° C. Then the mixture is evaporated down i.vac., the residue is combined with water and extracted with ethylacetate. The combined organic phases are dried over sodium sulphate,evaporated down i. vac. and the residue obtained is purified bychromatography on silica gel (eluting gradient: petroleum ether/ethylacetate 3:2->0:1).

Yield: 0.99 g (50%)

R_(t) value: 2.56 min

C₁₄H₁₇NO₄ (263.30)

Mass spectrum: (M+H)⁺=264

(c) 3-methoxy-4-(piperidin-2-on-1-yl)-benzoic acid

Prepared analogously to Example 39d from methyl3-methoxy-4-(piperidin-2-on-1-yl)-benzoate and lithium hydroxide inethanol.

Yield: 95%

R_(t) value: 0.10 (silica gel; petroleum ether/ethyl acetate=1:2)

C₁₃H₁₅NO₄ (249.27)

Mass spectrum: (M+H)⁺=250

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from3-methoxy-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in DMF and subsequentpurification by preparative HPLC.

Yield: 75%

R_(t) value: 2.35 min

C₂₂H₂₃ClN₄O₃*CF₃COOH (540.93/426.90)

Mass spectrum: (M+H)⁺=427/429 (chlorine isotope)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 70

Σ: 31% (M + H)⁺ = 457/459 (chlorine isotope) 2.31 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide 85

Σ: 0.8% (M + H)⁺ = 481/483 (chlorine isotope) 2.56 minN-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethoxy-benzamide 86

Σ: 6.2% (M + H)⁺ = 475/477/479 (bromine and chlorine isotope) 2.57 min3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-benzamide 87

Σ: 6.2% (M + H)⁺ = 505/507/509 (bromine and chlorine isotope) 2.57 min3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide

EXAMPLE 73N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thia-diazinan-2-yl)-3-methyl-benzamide

(a) methyl4-(1,1-dioxo-6-methyl-[1,2,6]-thiadiazinan-2-yl)-3-methyl-benzoate

400 mg (1.41 mmol) methyl4-(1,1-dioxo-[1,2,6]-thiadiazinan-2-yl)-3-methyl-benzoate dissolved in 4ml DMF at 40° C. are combined with 240 mg (2.14 mmol)potassium-tert.-butoxide and 96 μl (1.54 mmol) methyl iodide and stirredfor 5 hours at 40° C. The reaction solution is evaporated down i. vac.,combined with water and the aqueous phase is extracted with ethylacetate. The combined organic phases are dried over sodium sulphate andevaporated down i. vac.

Yield: 220 mg (52%)

C₁₃H₁₈N₂O₄S (298.36)

Mass spectrum: (M+H)⁺=299

R_(f) value: 0.44 (silica gel; petroleum ether/ethyl acetate=3:2)

(b) 4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoicacid

Prepared analogously to Example 39d from methyl4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoate andlithium hydroxide in ethanol.

Yield: (81%)

C₁₂H₁₆N₂O₄S (284.34)

Mass spectrum: (M+H)⁺=285

R_(f) value: 0.07 (silica gel; dichloromethane/methanol=19:1)

(c)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMFwith subsequent purification by preparative HPLC.

Yield: 55%

C₂₁H₂₄ClN₅O₃S*CF₃COOH (576.00/461.97)

Mass spectrum: (M+H)⁺=462/464 (chlorine isotope)

R_(t) value: 2.50 min

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(t) value No. Name 74

Σ: 20% (M + H)⁺ = 492/494 (chlorine isotope) 2.56 minN-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide

EXAMPLE 75N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-bromo-phenyl)-N-Boc-(S)—O-methyl-serinamide andN′-(2-amino-5-bromo-phenyl)-N-Boc-(S)—O-methyl-serinamide

2.50 g (6.24 mmol) of the dicyclohexylammonium salt ofN-Boc-(S)—O-methyl-serine are dissolved in 20 ml 5% citric acid, theaqueous phase is extracted 2× with 20 ml of ethyl acetate, the combinedorganic phases are dried over sodium sulphate and freed from solvent i.vac. The residue is dissolved together with 1.23 g (6.55 mmol)4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol)triethylamine and 4.97 ml (7.80 mmol) of a 50% solution of PPA in ethylacetate are added with stirring in the ice bath. After 5 minutesstirring in the ice bath the mixture is heated to ambient temperatureand stirred for 23 hours at ambient temperature. The reaction mixture ispoured into 100 ml of water and the aqueous phase is extracted withethyl acetate. The combined organic phases are extracted with sat.sodium carbonate solution and water, dried over sodium sulphate andevaporated down i. vac.

Yield: 2.38 g (98%) mixture of the two regioisomers

C₁₅H₂₂BrN₃O₄ (388.26)

Mass spectrum: (M+H)⁺=388/390 (bromine isotope)

R_(f) value: 0.63/0.68 (silica gel; dichloromethane/ethanol=9:1)

(b) (1R)—N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine

2.38 g (6.13 mmol) of the mixture obtained in 75a are dissolved in 150ml of toluene and 1.84 ml (30.7 mmol) acetic acid and 4.00 g molecularsieve, 3A, are added. The reaction mixture is stirred for 3 hours at 55°C. and then cooled for 15 minutes in the ice bath. The reaction mixtureis filtered and poured into a mixture of 500 ml each of water and ethylacetate. After vigorous mixing the organic phase is separated off,washed with sat. sodium chloride solution, dried over sodium sulphateand evaporated down i. vac. The residue is purified by chromatography onsilica gel (eluting gradient: dichloromethane/ethanol 100:0->97:3).

Yield: 1.40 g (62%)

C₁₅H₂₀BrN₃O₃ (370.24)

Mass spectrum: (M+H)⁺=370/372 (bromine isotope)

R_(f) value: 0.81 (silica gel; dichloromethane/ethanol=9:1)

(c) (1R)-1-(5-bromo-1H-benzimidazole-1-yl)-2-methoxy-ethylamine

Prepared analogously to Example 1g from(1R)—N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine and TFAin dichloromethane.

Yield: 51%

C₁₀H₁₂BrN₃O (270.13)

Mass spectrum: (M+H)⁺=270/272 (bromine isotope)

R_(f) value: 0.20 (silica gel, dichloromethane/ethanol 9:1)

(d)N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid,(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU andDIPEA in THF with subsequent purification by chromatography on silicagel.

Yield: quant.

C₂₂H₂₃BrN₄O₄ (487.35)

Mass spectrum: (M+H)⁺=487/489 (bromine isotope)

R_(f) value: 0.56 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 76N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate

5.00 g (11.3 mmol)dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butanoateare stirred into in 100 ml of 5% citric acid solution and then extractedwith ethyl acetate. The combined organic phases are dried over sodiumsulphate and the solvent is distilled off i. vac. The residue isdissolved in 70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol)DIPEA are added and the mixture is stirred for 10 minutes at ambienttemperature. Then 50 ml of ethanol are added and the mixture is refluxedfor 16 hours. Then the reaction mixture is evaporated down i. vac.,taken up in ethyl acetate, washed with semisaturated sodium hydrogencarbonate solution and water, dried over sodium sulphate and evaporateddown i. vac.

Yield: 3.20 g (98%)

C₁₅H₁₈N₂O₄ (290.32)

Mass spectrum: (M+NH₄)⁺=308

R_(f) value: 0.80 (silica gel; dichloromethane/ethanol=9:1)

(b) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyrate

3.20 g (11.0 mmol) ethyl(2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate are dissolved in 40 mlof toluene and 1.08 g (16.5 mmol) sodium azide and 2.28 g (16.5 mmol)triethylamine-hydrochloride are added. The reaction mixture is heated to85° C. for 24 hours, cooled to ambient temperature and extracted withwater. The combined aqueous phases are acidified to pH 2 with semiconc.hydrochloric acid, the resulting precipitate is suction filtered, washedwith water and dried at 50° C.

Yield: 2.90 g (79%)

C₁₅H₁₉N₅O₄ (333.34)

Mass spectrum: (M+H)⁺=334

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

(c) (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyric acid

Prepared analogously to Example 30b from ethyl(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyrate andlithium hydroxide in a mixture of solvents from water and THF.

Yield: quant.

C₁₃H₁₅N₅O₄ (305.29)

Mass spectrum: (M+H)⁺=306

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=4:1)

(d)N′-(2-amino-4-chloro-phenyl)-(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyricacid amide andN′-(2-amino-5-chloro-phenyl)-(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyricacid amide

Prepared analogously to Example 47a from(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyric acid and4-chloro-1,2-phenylenediamine with DCC in THF.

Yield: quant., mixture of the two regioisomers, slightly contaminatedC₁₉H₂₀ClN₇O₃ (429.86)

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=9:1)

(e)(1S)—N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine

Prepared analogously to Example 47b from the product obtained in Example76d and acetic acid.

Yield: quant.

C₁₃H₁₈ClN₇O₂*CH₃COOH (471.90/411.85)

R_(f) value: 0.25 (silica gel; dichloromethane/ethanol/conc.ammonia=4:1:0.1)

(f)(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine

2.10 g (4.45 mmol)(1S)—N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylaminein 30 ml dichloromethane are combined with 1.9 ml (13.4 mmol)iodo-trimethylsilane and stirred for 16 hours at ambient temperature.Then 20 ml of methanol are added, the mixture is stirred for a further30 minutes at ambient temperature and the reaction mixture is evaporateddown completely i. vac. The residue is purified by chromatography onsilica gel (eluting gradient: dichloromethane/(ethanol/conc. ammonia95:5)=70/30->60:40).

Yield: 690 mg (56%)

C₁₁H₁₂ClN₇ (277.71)

Mass spectrum: (M+H)⁺=278/280 (chlorine isotope)

R_(f) value: 0.15 (silica gel; dichloromethane/ethanol=3:2+1% conc.ammonia)

(g)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine,TBTU and DIPEA in THF with subsequent purification by chromatography onsilica gel.

Yield: 33%

C₂₃H₂₃ClN₈O₃ (494.93)

Mass spectrum: (M+H)⁺=495/497 (chlorine isotope)

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=4:1)

EXAMPLE 77N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-(2S)-2-(Boc-amino)-3-methoxy-propionicacid amide andN′-(2-amino-5-chloro-phenyl)-(2S)-2-(Boc-amino)-3-methoxy-propionic acidamide

4.90 g (21.0 mmol) (2S)-2-(Boc-amino)-3-methoxy-propionic acid aredissolved in 20 ml THF and combined with 13.57 g (42.0 mmol) TBTU and5.76 ml (52.5 mmol) triethylamine and stirred for 30 minutes at ambienttemperature. Then 3.00 g (21.0 mmol) 4-chloro-1,2-phenylenediamine in 20ml THF are added and the mixture is stirred for 16 hours at ambienttemperature. Then the reaction mixture is evaporated down i. vac.,poured into water and extracted with ethyl acetate. The combined organicphases are washed with sat. sodium hydrogen carbonate solution, driedover sodium sulphate and evaporated down i. vac. The residue is purifiedby chromatography on silica gel (eluant: dichloromethane/methanol 99:1).

Yield: 5.60 g (75%) mixture of the two regioisomers

C₁₆H₂₄ClN₃O₃ (357.83)

Mass spectrum: (M+H)⁺=358/360 (chlorine isotope)

R_(f) value: 0.26 (silica gel; dichloromethane/methanol=99:1)

(b) (1S)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine

Prepared analogously to Example 47b from the product obtained in Example77a and acetic acid.

Yield: 96%

C₁₆H₂₂ClN₃O₃ (339.82)

Mass spectrum: (M+H)⁺=340/342 (chlorine isotope)

R_(f) value: 0.80 (silica gel; dichloromethane/methanol=19:1)

(c) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine

Prepared analogously to Example 1g from(1S)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine andTFA in dichloromethane.

Yield: 31%

C₁₁H₁₄ClN₃O (239.70)

Mass spectrum: (M+H)⁺=240/242 (chlorine isotope)

R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=9:1)

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine, TBTU andDIPEA in THF with subsequent purification by chromatography on silicagel.

Yield: 59%

C₂₃H₂₅ClN₄O₄ (456.92)

Mass spectrum: (M+H)⁺=457/459 (chlorine isotope)

R_(f) value: 0.51 (silica gel; dichloromethane/ethanol=9:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 148

Σ: 57% (M + H)⁺ = 427/429 (chlorine isotope) 0.5 (silica gel;dichloromethane/ ethanol = 9:1)N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-methyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 88

Σ: 3.6% (M + H)⁺ = 465/467 (chlorine isotope) 2.38 minN-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(furan-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

EXAMPLE 823-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide

(a) methyl 3-chloro-4-nitroso-benzoate

8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml ofconc. sulphuric acid with stirring, stirred for 30 minutes at ambienttemperature under a nitrogen atmosphere, the mixture is stirred into 50g ice and neutralised with 14 g sodium carbonate. The solution obtainedis combined with a suspension of 2.78 g (15.0 mmol) methyl4-amino-3-chloro-benzoate in 300 ml of water and stirred for 16 hours atambient temperature. The reaction mixture is suction filtered, thefilter cake is washed with water, dried in the air and purified bychromatography on silica gel (eluant: petroleum ether/ethyl acetate9:1).

Yield: 1.00 g (33%)

C₈H₆ClNO₃ (199.59)

Mass spectrum: (M+H)⁺=199/201 (chlorine isotope)

R_(f) value: 0.55 (silica gel; petroleum ether/ethyl acetate=4:1)

(b) methyl 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoate

1.00 g (5.01 mmol) methyl 3-chloro-4-nitroso-benzoate are placed in 10ml chloroform and a freshly prepared solution of 1.10 g (20.3 mmol)butadiene in 6 ml chloroform is added dropwise with stirring at 0° C.The reaction mixture is stirred for 30 minutes at 0-10° C. and for 16hours at ambient temperature, evaporated down i. vac. and purified bychromatography on silica gel (eluant: petroleum ether/ethylacetate=19:1).

Yield: 1.00 g (79%)

C₁₂H₁₂ClNO₃ (253.68)

Mass spectrum: (M+H)⁺=254/256 (chlorine isotope)

R_(f) value: 0.50 (silica gel; petroleum ether/ethyl acetate=4:1)

(c) 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoic acid

Prepared analogously to Example 2d from methyl3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoate and sodium hydroxidein a solvent mixture of water and ethanol.

Yield: 90%

C₁₁H₁₀ClNO₃ (239.66)

Mass spectrum: (M−H)⁻=238/240

R_(f) value: 0.20 (silica gel; petroleum ether/ethyl acetate=4:1)

(d)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF.

Yield: 88%

C₂₀H₁₈Cl₂N₄O₂ (417.29)

Mass spectrum: (M+H)⁺=417/419/421 (chlorine isotope)

R_(f) value: 0.35 (silica gel; petroleum ether/ethyl acetate=1:1)

EXAMPLE 833-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide

(a) 2-chloro-N-(4-chlorbutyl-sulphonyl)-4-methyl-aniline

1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml ofpyridine, combined with 2.67 g (10.5 mmol) 75% m 4-chlorobutyl-sulphonicacid chloride and stirred for 16 hours at ambient temperature. Thereaction mixture is poured into water and extracted with ethyl acetate.The combined organic phases are washed with 6-molar hydrochloric acid,dried over sodium sulphate and evaporated down i. vac. The residue ispurified by chromatography on silica gel (eluting gradient: petroleumether/ethyl acetate=9:1->7:3).

Yield: 1.27 g (40%)

C₁₁H₁₅Cl₂NO₂S (296.21)

Mass spectrum: (M+H)⁺=296/298/300 (chlorine isotope)

R_(f) value: 0.42 (silica gel; petroleum ether/ethyl acetate=4:1)

(b) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-toluene

1.27 g (4.29 mmol) 2-chloro-N-(4-chlorbutyl-sulphonyl)-4-methyl-anilineare stirred together with 722 mg (6.43 mmol) potassium-tert.-butoxide in50 ml DMF for 16 hours at 60° C. Then the reaction mixture is pouredinto water and extracted with ethyl acetate. The combined organic phasesare dried over sodium sulphate and evaporated down i. vac. The residueis purified by chromatography on silica gel (eluant: petroleumether/ethyl acetate=3:2).

Yield: 850 mg (76%)

C₁₁H₁₄ClNO₂S (259.75)

Mass spectrum: (M+H)⁺=260/262 (chlorine isotope)

R_(f) value: 0.27 (silica gel; petroleum ether/ethyl acetate=4:1)

(c) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzoic acid

250 mg (0.96 mmol) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-tolueneare suspended in 10 ml of water and combined with 456 mg (2.89 mmol)potassium permanganate and 39 mg (0.98 mmol) sodium hydroxide. Thereaction mixture is refluxed for 4 hours. After cooling to ambienttemperature sodium thiosulphate is added to decolorise the mixture whichis then extracted with ethyl acetate. The combined organic phases aredried over sodium sulphate and evaporated down i. vac. The residue ispurified by chromatography on silica gel (eluant:dichloromethane/methanol=19:1).

Yield: 50 mg (18%)

C₁₁H₁₂ClNO₄S (289.74)

Mass spectrum: (M+H)⁺=290/292

R_(t) value: 2.50 min

(d)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(1,2-dioxo-[1,2]thiazinan-2-yl)-benzoic acid,(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU andNMM in DMF with subsequent purification by preparative HPLC.

Yield: 34%

C₂₁H₂₂Cl₂ N₄O₄S (497.40)

Mass spectrum: (M+H)⁺=497/499/501 (chlorine isotope)

R_(t) value: 2.53 min

EXAMPLE 84N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide

(a) methyl 4-(5-chloropentyl-sulphonyl-amino)-3-methyl-benzoate

Prepared analogously to Example 83a from methyl4-amino-3-methyl-benzoate and 5-chloropentyl-sulphonic acid chloride inpyridine. Yield: 43%

C₁₄H₂₀ClNO₄S (333.83)

Mass spectrum: (M+H)⁺=334/336 (chlorine isotope)

R_(f) value: 0.72 (silica gel; petroleum ether/ethyl acetate=7:3)

(b) methyl 4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoate

Prepared analogously to Example 83b from methyl4-(5-chloropentyl-sulphonyl-amino)-3-methyl-benzoate andpotassium-tert.-butoxide in DMF.

Yield: 19%

C₁₄H₁₉NO₄S (297.37)

Mass spectrum: (M+H)⁺=298

R_(t) value: 0.30 (silica gel; petroleum ether/ethyl acetate=4:1)

(c) 4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoic acid

Prepared analogously to Example 39d from methyl4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoate and lithiumhydroxide in a solvent mixture of water and ethanol.

Yield: 60%

C₁₃H₁₇NO₄S (283.34)

Mass spectrum: (M+H)⁺=284

R_(t) value: 2.60 min

(d)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from4-(1,2-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoic acid,(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU andNMM in DMF with subsequent purification by chromatography on silica gel.

Yield: 75%

C₂₃H₂₇ClN₄O₄S (491.00)

Mass spectrum: (M+H)⁺=491/493 (chlorine isotope)

R_(t) value: 2.60 min

EXAMPLE 893-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,2]oxazinan-2-yl)-benzamide

209 mg (0.50 mmol)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamidetogether with 100 mg 10% palladium charcoal in 5 ml of ethyl acetate for7 minutes are hydrogenated at ambient temperature at 5 bar under ahydrogen atmosphere. Then the mixture is suction filtered, the filtrateis evaporated down i. vac. and evaporated again with ether.

Yield: 200 mg (95%)

C₂₀H₂₀Cl₂N₄O₂ (419.30)

Mass spectrum: (M+H)⁺=419/421/423 (chlorine isotope)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=1:1)

EXAMPLE 90N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide

(a) ethyl 3-(2-benzyloxy-ethoxy)-propionate

8.53 ml (60.0 mmol) benzyloxy-ethanol are combined with 13 mg (0.57mmol) sodium in 40 ml THF, then when it has dissolved 5.95 ml (54.7mmol) ethyl acrylate are added under an argon atmosphere and stirred for20 hours at ambient temperature. After neutralising with 0.6 ml 1-molarhydrochloric acid the reaction mixture is evaporated down i. vac., theresidue is taken up in sat. sodium chloride solution and extracted withethyl acetate. The combined organic phases are washed with sat. sodiumchloride solution, dried over sodium sulphate and evaporated down i.vac. The residue is purified by chromatography on silica gel (eluant:petroleum ether/ethyl acetate=4:1).

Yield: 3.73 g (25%)

C₁₄H₂₀O₄ (252.31)

Mass spectrum: (M+H)⁺=253

R_(f) value: 0.48 (silica gel; petroleum ether/ethyl acetate=4:1)

(b) ethyl 3-(2-hydroxy-ethoxy)-propionate

3.73 g (14.8 mmol) ethyl 3-(2-benzyloxy-ethoxy)-propionate arehydrogenated together with 665 mg 10% palladium charcoal in 70 ml ofethanol for 44 minutes at ambient temperature under a hydrogenatmosphere at 3 bar. Then the mixture is suction filtered and thefiltrate is evaporated down i. vac.

Yield: 2.26 g (94%)

C₇H₁₄O₄ (162.18)

Mass spectrum: (M+H)⁺=163

(c) ethyl 3-(2-chloro-ethoxy)-propionate

2.26 g (13.9 mmol) ethyl 3-(2-hydroxy-ethoxy)-propionate are suspendedin 5 ml (68.5 mmol) thionyl chloride and 20 μl (0.27 mmol) DMF areadded. The reaction mixture is refluxed for 4 hours and then evaporateddown i. vac. The product is further reacted without any morepurification.

Yield: quant.

C₇H₁₃O₃ (180.63)

Mass spectrum: (M+H)⁺=181/183 (chlorine isotope)

(d) 3-(2-chloro-ethoxy)-propionic acid

2.00 g (11.1 mmol) ethyl 3-(2-chloro-ethoxy)-propionate are suspended in8 ml of ethanol and 4.96 ml (16.6 mmol) of 8% lithium hydroxide solutionare added. The mixture is stirred for 4 hours at ambient temperature,then evaporated down i. vac., acidified with 2-molar hydrochloric acid,combined with diethyl ether and dried over sodium sulphate. Then it isfiltered off and evaporated down i. vac.

Yield: 1.51 g (89%)

C₅H₉ClO₃ (152.58)

Mass spectrum: (M−Hy=151/153 (chlorine isotope)

(e) 3-(2-chloro-ethoxy)-propionic acid-chloride

Prepared analogously to Example 90c from 3-(2-chloro-ethoxy)-propionicacid and thionyl chloride with DMF.

Yield: 91%

C₅H₈Cl₂O₂ (171.02)

(f) methyl 4-[3-(2-chloro-ethoxy)-propionyl-amino]-3-methyl-benzoate

1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF arecombined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20minutes at ambient temperature. Then a solution of 1.78 g (10.4 mmol)3-(2-chloro-ethoxy)-propionic acid-chloride in 25 ml THF is addeddropwise and the mixture is stirred for a further 2.5 hours at ambienttemperature. Then water is added and the mixture is extracted with ethylacetate. The combined organic phases are dried over sodium sulphate andevaporated down completely i. vac. The residue is purified bychromatography on silica gel (eluting gradient: petroleum ether/ethylacetate=7:3->6:4).

Yield: 1.25 g (41%)

C₁₄H₁₈ClNO₄ (299.75)

Mass spectrum: (M+H)⁺=300/302 (chlorine isotope)

R_(f) value: 0.15 (silica gel; petroleum ether/ethyl acetate=7:3)

(g) methyl 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoate

900 mg (3.00 mmol)4-[3-(2-chloro-ethoxy)-propionyl-amino]-3-methyl-benzoate methyl arestirred in 40 ml DMF together with 520 mg (4.63 mmol) potassiumtert.-butoxide and 12 mg (80 μmol) sodium iodide for 3 hours at 60° C.After evaporation i. vac. the residue is combined with water, extractedwith ethyl acetate and the combined organic phases are dried over sodiumsulphate and evaporated down i. vac. The residue is purified bychromatography on silica gel (eluant: petroleum ether/ethylacetate=11:9).

Yield: 310 mg (39%)

C₁₄H₁₇NO₄ (263.29)

Mass spectrum: (M+H)⁺=264

(h) 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoic acid

Prepared analogously to Example 39d from methyl3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoate and lithium hydroxide ina solvent mixture of water and ethanol.

Yield: 69%

C₁₃H₁₅NO₄ (249.26)

Mass spectrum: (M+H)⁺=250

R_(t) value: 2.06 min

(i)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoic acid,(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU andNMM in DMF with subsequent purification by preparative HPLC.

Yield: 83%

C₂₃H₂₅ClN₄O₄ (456.92)

Mass spectrum: (M+H)⁺=457/459 (chlorine isotope)

R_(t) value: 2.23 min

EXAMPLE 91N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide

(a) methyl 4-(3-[1,1-dimethyl-2-hydroxy-ethyl]ureido)-3-methyl-benzoate

5.70 g (29.8 mmol) methyl 4-isocyanato-3-methyl-benzoate are dissolvedin 100 ml THF and a solution of 2.86 ml (30.0 mmol)2-amino-2-methyl-propan-1-ol in 25 ml THF is added dropwise. The mixtureis stirred for 2 hours at ambient temperature and then evaporated downi. vac. The residue is further reacted without any more purification.

Yield: 8.40 g (quant.)

C₁₄H₂₀N₂O₄ (280.32)

Mass spectrum: (M−H)⁻=279

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=19:1)

(b) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoate

7.00 g (25.0 mmol) methyl4-(3-[1,1-dimethyl-2-hydroxy-ethyl]-ureido)-3-methyl-benzoate aredissolved in 400 ml THF at 0° C. and combined with 6.73 g (60.0 mmol)potassium-tert.-butoxide. After stirring for 15 minutes at 0° C. asolution of 5.72 g (30.0 mmol) p-toluenesulphonic acid in 50 ml THF isadded dropwise. After another 10 minutes stirring at 0° C. 300 ml ofwater are added, the mixture is neutralised with 1-molar hydrochloricacid and the THF is removed i. vac. The residue is extracted withdichloromethane. The combined organic phases are dried over sodiumsulphate and evaporated down i. vac. Then the residue is purified bychromatography on silica gel (eluting gradient:dichloromethane/ethanol=100:0->97:3).

Yield: 2.50 g (38%)

C₁₄H₁₈N₂O₃ (262.30)

Mass spectrum: (M+H)⁺=263

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=19:1)

(c) 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoic acid

2.70 g (10.3 mmol) methyl4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoate are suspendedin 75 ml of methanol and combined with a solution of 1.68 g (30.0 mmol)potassium hydroxide in 10 ml of water. It is stirred for 3 hours atambient temperature and then evaporated down i. vac. The aqueous residueis diluted with water, acidified with 1-molar hydrochloric acid and theprecipitate obtained is suction filtered, washed with water and dried.

Yield: 2.30 g (90%)

C₁₃H₁₆N₂O₃ (248.28)

Mass spectrum: (M+H)⁺=249

R_(f) value: 0.50 (silica gel; dichloromethane/methanol=9:1)

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

Prepared analogously to Example 1f from4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THFand purification of the residue by chromatography on silica gel.

Yield: 59%

C₂₂H₂₄ClN₅O₂ (425.91)

Mass spectrum: (M+H)⁺=426/428 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/methanol=9:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value No. Name 92

Σ: 29% (M + H)⁺ = 456/458 (chlorine isotope) 0.45 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide

EXAMPLE 933-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide

(a) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzonitrile

4.00 g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60° C.in 20 ml DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirringfor 2 hours. Then the reaction mixture is poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and sat. sodium chloride solution, dried over sodium sulphateand evaporated down i. vac.

Yield: 5.20 g (96%)

C₁₀H₁₁ClN₂O (210.66)

Mass spectrum: (M+H)⁺=211/213 (chlorine isotope)

R_(f) value: 0.27 (silica gel; dichloromethane/methanol=19:1)

(b) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoic acid

5.20 g (24.7 mmol)3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzonitrile are refluxed for6 hours in 50 ml of conc. hydrochloric acid with stirring. Then themixture is evaporated down i. vac., made basic with conc. ammoniasolution and extracted with ethyl acetate. After acidification of theaqueous phase with acetic acid the mixture is extracted with ethylacetate, the combined organic phases are washed with water and sat.sodium chloride solution, dried over sodium sulphate and evaporated downi. vac.

Yield: 5.00 g (88%)

C₁₀H₁₂ClNO₃ (229.66)

Mass spectrum: (M+H)⁺=230/232 (chlorine isotope)

R_(f) value: 0.44 (silica gel; dichloromethane/methanol=9:1)

(c) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate

5.00 g (21.8 mmol) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoicacid are stirred for 16 hours in 100 ml sat. ethanolic hydrochloric acidat ambient temperature and then evaporated down i. vac. The residue iscombined with water and conc. ammonia solution and extracted with ethylacetate. The combined organic phases are washed with water and sat.sodium chloride solution, dried over sodium sulphate and evaporated downi. vac. The residue is purified by chromatography on silica gel (eluant:dichloromethane/methanol=50:1).

Yield: 3.40 g (61%)

C₁₂H₁₆ClNO₃ (257.71)

Mass spectrum: (M+H)⁺=258/260 (chlorine isotope)

R_(f) value: 0.34 (silica gel; dichloromethane/methanol=19:1)

(d) ethyl 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate

0.50 g (1.94 mmol) ethyl3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are placed in 30 mlTHF together with 0.22 g (2.20 mmol) triethylamine and 1.10 ml (2.08mmol) 20% phosgene solution in toluene is added with stirring at ambienttemperature. The mixture is stirred for 1 hour at ambient temperature,then 1 ml of water is added and the mixture is stirred for another 10minutes. The mixture is then evaporated down i. vac., combined withwater and extracted with ethyl acetate. The combined organic phases arewashed with water and sat. sodium chloride solution, dried over sodiumsulphate and evaporated down i. vac.

Yield: 0.54 g (98%)

C₁₃H₁₄ClNO₄ (283.71)

Mass spectrum: (M+H)⁺=284/286 (chlorine isotope)

R_(f) value: 0.71 (silica gel; dichloromethane/methanol=19:1)

(e) 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoic acid

0.90 g (3.17 mmol) ethyl3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate are stirred for 1hour in 50 ml of methanol with 10 ml 1-molar aqueous lithium hydroxidesolution at ambient temperature. The mixture is then evaporated down to20 ml i. vac., acidified with conc. hydrochloric acid and extracted withethyl acetate. The combined organic phases are washed with sat. sodiumchloride solution, dried over sodium sulphate and evaporated down i.vac. The residue is crystallised from a little diethyl ether and suctionfiltered.

Yield: 0.45 g (56%)

C₁₁H₁₀ClNO₄ (255.65)

Mass spectrum: (M+H)⁺=256/258 (chlorine isotope)

R_(f) value: 0.26 (silica gel; dichloromethane/methanol=9:1)

(f)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THFand purification of the residue by chromatography on aluminium oxide.

Yield: 45%

C₂₀H₁₈Cl₂N₄O₃ (433.29)

Mass spectrum: (M+H)⁺=433/435/437 (chlorine isotope)

R_(f) value: 0.65 (silica gel; dichloromethane/methanol=9:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 94

Σ: 18% (M + H)⁺ = 463/465/467 (chlorine isotope) 0.60 (silica gel,CH₂Cl₂/ CH₃OH 19:1)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide 102

Σ: 18% (M + H)⁺ = 443/445 (chlorine isotope) 0.20 (silica gel, CH₂Cl₂/CH₃OH 19:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-((4S)-4-methyl-2-oxo-oxazolidin-3-yl)-benzamide 103

Σ: 9.4% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.30 (silica gel,CH₂Cl₂/ CH₃OH 19:1)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide 104

Σ: 13% (M + H)⁺ = 443/445 (chlorine isotope) 0.80 (silica gel, CH₂Cl₂/CH₃OH 19:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-((4R)-4-methyl-2-oxo-oxazolidin-3-yl)-benzamide 105

Σ: 18% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.65 (silica gel,CH₂Cl₂/ CH₃OH 19:1)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-((4R)-4-ethyl-2-oxo-oxazolidin-3-yl)-benzamide

EXAMPLE 95

N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-N-Boc-phenyl-glycinamide andN′-(2-amino-5-chloro-phenyl)-N-Boc-phenyl-glycinamide

Prepared analogously to Example 47a from N-Boc-phenyl-glycine,4-chloro-1,2-phenylenediamine and DCC in THF.

Yield: quant. mixture of the two regioisomers

C₁₉H₂₂ClN₃O₃ (375.85)

Mass spectrum: (M+H)⁺=376/378 (chlorine isotope)

R_(f) value: 0.41 (silica gel; dichloromethane/ethanol=19:1)

(b) N-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine

3.65 g (9.71 mmol) of the mixture obtained in 95a are dissolved in 8 mlacetic acid and refluxed for 6 hours with stirring. The reaction mixtureis evaporated down i. vac. and the residue is purified by chromatographyon silica gel (eluting gradient: dichloromethane/ethanol=100:0->94:6).

Yield: 1.34 g (46%)

C₁₆H₁₄ClN₃O (299.76)

Mass spectrum: (M+H)⁺=300/302 (chlorine isotope)

R_(f) value: 0.19 (silica gel; dichloromethane/ethanol=19:1)

(c) 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine

1.34 g (4.47 mmol)N-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine in 9 mlof ethanol are combined with 18 ml of conc. hydrochloric acid and heatedto 50° C. for 2 days. The reaction mixture is evaporated down i. vac.and twice taken up in ethanol and evaporated down again.

Yield: 1.26 g (96%)

C₁₄H₁₂ClN₃*HCl (294.18/257.72)

Mass spectrum: (M+H)⁺=258/260 (chlorine isotope)

(d)N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid,1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine, TBTU and DIPEAin THF.

Yield: 89%

C₂₆H₂₃ClN₄O₃ (474.94)

Mass spectrum: (M+H)⁺=475/477 (chlorine isotope)

R_(f) value: 0.68 (silica gel; dichloromethane/ethanol=9:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 108

Σ: 12% (M + H)⁺ = 437/439 (chlorine isotope) 0.51 (silica gel, CH₂Cl₂/ethanol = 9:1)N-[1-(1S)-(5-chloro-1H-benzimidazol-2-yl)-2-cyano-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 140

Σ: 2.9% (M + H)⁺ = 455/457 (chlorine isotope) 0.60 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

EXAMPLE 96N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-(2S)-2-(Boc-amino)-butyric acid amideand N′-(2-amino-5-chloro-phenyl)-(2S)-2-(Boc-amino)-butyric acid amide

Prepared analogously to Example 47a from (2S)-2-(Boc-amino)-butyricacid, 4-chloro-1,2-phenylenediamine and DCC in THF.

Yield: 89% mixture of the two regioisomers

C₁₅H₂₂ClN₃O₃ (327.81)

Mass spectrum: (M+H)⁺=328/330 (chlorine isotope)

R_(f) value: 0.63 (silica gel; dichloromethane/ethanol=19:1)

(b) (1S)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine

Prepared analogously to Example 47b from the mixture obtained in 95a andacetic acid and purification of the residue by chromatography on silicagel.

Yield: 94%

C₁₅H₂₀ClN₃O₂ (309.79)

Mass spectrum: (M+H)⁺=310/312 (chlorine isotope)

R_(f) value: 0.63 (silica gel; dichloromethane/ethanol=19:1)

(c) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine

Prepared analogously to Example 75c from(1S)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine andtrifluoroacetic acid in dichloromethane.

Yield: quant.

C₁₀H₁₂ClN₃*2 CF₃COOH (437.72/209.68)

Mass spectrum: (M+H)⁺=210/212 (chlorine isotope)

(d)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid,(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA inTHF.

Yield: 17%

C₂₂H₂₃ClN₄O₃ (426.90)

Mass spectrum: (M+H)⁺=427/429 (chlorine isotope)

R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=9:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 107

Σ: 4.0% (M + H)⁺ = 465/467 (chlorine isotope) 0.15 (silica gel, CH₂Cl₂/CH₃OH 9:1)N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 141

Σ: 62% (M − H)⁻ = 519/521 (chlorine isotope) 0.54 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-benzyloxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide 149

Σ: 54% (M − H)⁻ = 453/455 (chlorine isotope) 0.55 (silica gel, CH₂Cl₂/C₂H₅OH 9:1)N-[3-(5-chloro-1H-benzimidazol-2-yl)-tetrahydrofuran-3-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

EXAMPLE 106N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide

(a) ethyl 4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate

Prepared analogously to Example 46a from(2-chloro-ethoxy)-acetylchloride and ethyl 4-amino-3-fluoro-benzoatewith TEA in THF.

Yield: 44%

C₁₃H₁₅ClFNO₄ (303.71)

Mass spectrum: (M+H)⁺=304/306 (chlorine isotope)

R_(f) value: 0.29 (silica gel; dichloromethane)

(b) 4-(2-carboxymethoxy-ethylamino)-3-fluoro-benzoic acid

580 mg (1.91 mmol) ethyl4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate in 6 ml dioxane arecombined with 3.82 ml (7.64 mmol) 2-molar potassium hydroxide solutionand 2 ml of water. Then the mixture is heated to 70° C. for 2 h, thendiluted with water and acidified with 6-molar hydrochloric acid. Afterthe addition of dichloromethane the precipitate formed is suctionfiltered and dried in the drying cupboard at 50° C.

Yield: 390 mg (79%)

C₁₁H₁₂FNO₅ (257.22)

Mass spectrum: (M+H)⁺=258

R_(f) value: 0.66 (reversed phase RP-8; methanol/5/0 NaCl solution=6:4)

(c) 3-fluoro-4-(morpholin-3-on-4-yl)-benzoic acid-chloride

Prepared analogously to Example 41c from4-(2-carboxymethoxy-ethylamino)-3-fluoro-benzoic acid andthionylchloride in dichloromethane with DMF.

Yield: quant.

C₁₁H₉CIFNO₃ (257.65)

(d)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 41d from3-fluoro-4-(morpholin-3-on-4-yl)-benzoic acid-chloride and(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TEA inTHF.

Yield: 47%

C₂₁H₂₀ClFN₄O₄ (446.86)

Mass spectrum: (M+H)⁺=447/449 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 109N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-2-(Boc-amino)-2-(pyridin-3-yl)-aceticacid amide andN′-(2-amino-5-chloro-phenyl)-2-(Boc-amino)-2-(pyridin-3-yl)-acetic acidamide

1.00 g (3.96 mmol) N-Boc-amino-2-(pyridin-3-yl)-acetic acid are placedtogether with 0.59 g (4.16 mmol) 4-chloro-1,2-phenylenediamine at 0° C.in 20 ml THF and 2.92 ml (4.96 mmol) 50% PPA solution in ethyl acetateand 1.24 ml (8.92 mmol) TEA are added. After stirring for 30 min at 0°C. the mixture is stirred for 5 h at ambient temperature stirred andthen evaporated down completely i. vac. The residue is purified bychromatography on silica gel (eluting gradient:dichloromethane/ethanol=10:0->9:1).

Yield: 1.32 g (88%) mixture of the two regioisomers

C₁₈H₂₁ClN₄O₃ (376.84)

Mass spectrum: (M+H)⁺=377/379 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=9:1)

(b) N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine

Prepared analogously to Example 47b from the product obtained in Example111a and acetic acid.

Yield: 81%

C₁₈H₁₉ClN₄O₂ (358.82)

Mass spectrum: (M+H)⁺=359/361 (chlorine isotope)

R_(f) value: 0.51 (silica gel; dichloromethane/ethanol=9:1)

(c) 1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine

Prepared analogously to Example 1g fromN-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine andtrifluoroacetic acid in dichloromethane.

Yield: 66%

C₁₃H₁₁ClN₄ (258.71)

Mass spectrum: (M+H)⁺=259/261 (chlorine isotope)

R_(f) value: 0.62 (silica gel; dichloromethane/ethanol=9:1)

(d)N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine with TBTUand DIPEA in THF.

Yield: 84%

C₂₅H₂₂ClN₅O₃ (475.93)

Mass spectrum: (M+H)⁺=476/478 (chlorine isotope)

R_(f) value: 0.31 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 110

N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-yl]-acetate

5.00 g (20.7 mmol) ethoxycarbonyl-methoxyimino-(pyrazol-3-yl)-aceticacid are placed in 20 ml DMF together with 5.73 g (41.5 mmol) potassiumcarbonate at ambient temperature, stirred until the development of gashas ended, then 2.58 ml (41.5 mmol) of methyl iodide are added and themixture is stirred for 2 h at 50° C. After evaporation of the reactionmixture i. vac. the residue is combined with water and ethyl acetate,the organic phase is washed with water, dried over magnesium sulphateand evaporated down completely i. vac. The residue is purified bychromatography on silica gel (eluting gradient: petroleum ether/ethylacetate=80:20->65:35).

Yield: 2.61 g (26%) in admixture with regioisomers

C₁₁H₁₅N₃O₅ (269.25)

Mass spectrum: (M+H)⁺=270

R_(f) value: 0.25 (silica gel; petroleum ether/ethyl acetate=1:1)

(b) methyl 2-amino-2-(1-methyl-pyrazol-3-yl)-acetate

2.61 g (9.69 mmol) methylethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-yl)-acetate arehydrogenated in 60 ml of ethanol with 1.1 g 5% palladium charcoal for 16h at 50° C. under 3.4 bars pressure in a hydrogen atmosphere. Then themixture is suction filtered and the filtrate is evaporated downcompletely i. vac.

Yield: 1.90 g (quant.), slightly contaminated

C₇H₁₁N₃O₂ (169.18)

Mass spectrum: (M+H)⁺=170

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=9:1)

(c) methyl N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate

Prepared analogously to Example 1d from methyl2-amino-2-(1-methyl-pyrazol-3-yl)-acetate and di-tert. butylpyrocarbonate with TEA in dichloromethane.

Yield: 81%

C₁₂H₁₉N₃O₄ (269.30)

Mass spectrum: (M+H)⁺=270

(d) N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetic acid

1.16 g (4.31 mmol) methylN-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate in 16 ml THF arecombined with 10 ml of water and 10 ml of 1-molar lithium hydroxidesolution are added. After stirring at ambient temperature for 2 h themixture is evaporated down i. vac., the residue is combined with water,filtered and the filtrate is adjusted to pH 5 with potassium hydrogensulphate solution. After total evaporation i. vac. the residue istreated with dichloromethane and a little ethanol, suction filtered andthe filtrate is evaporated down completely i. vac.

Yield: 0.92 g (84%)

C₁₁H₁₇N₃O₄ (255.27)

Mass spectrum: (M+H)⁺=256

R_(f) value: 0.15 (silica gel; dichloromethane/ethanol=8:2)

(e)N′-(2-amino-4-chloro-phenyl)-2-(Boc-amino)-2-(1-methyl-pyrazol-3-yl)-aceticacid amide andN′-(2-amino-5-chloro-phenyl)-2-(Boc-amino)-2-(1-methyl-pyrazol-3-yl)-aceticacid amide

Prepared analogously to Example 111a fromN-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetic acid and4-chloro-1,2-phenylenediamine with PPA in ethyl acetate and NMM indichloromethane.

Yield: 55% mixture of the two regioisomers

C₁₇H₂₂ClN₅O₃ (379.84)

R_(f) value: 0.61 (silica gel; dichloromethane/ethanol=9:1)

(f)N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine

Prepared analogously to Example 47b from the product obtained in Example112e and acetic acid.

Yield: 81%

C₁₇H₂₀ClN₅O₂ (361.83)

Mass spectrum: (M+H)⁺=362/364 (chlorine isotope)

R_(f) value: 0.60 (silica gel; dichloromethane/ethanol=9:1)

(g)1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine

Prepared analogously to Example 1g fromN-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamineand trifluoroacetic acid in dichloromethane.

Yield: 77%

C₁₂H₁₂ClN₅ (261.71)

Mass spectrum: (M−NH₃+H)⁺=245/247 (chlorine isotope)

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol/conc. ammoniasolution=9:1:0.1)

(h)N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylaminewith TBTU and DIPEA in THF.

Yield: 38%

C₂₄H₂₃ClN₆O₃ (478.93)

Mass spectrum: (M+H)⁺=479/481 (chlorine isotope)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 1113-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide

(a) ethyl412-(tert.-butoxycarbonyl-methoxy)-1-methyl-ethylamino]-3-chloro-benzoate

1.12 g (4.35 mmol) ethyl3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are combined in 10ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride dispersion and stirredfor 5 min at ambient temperature. Then 0.67 ml tert.-butyl bromoacetateare added and the mixture is stirred for a further 16 h at ambienttemperature. Then the reaction mixture is poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and sat. sodium chloride solution, dried over sodium sulphateand evaporated down completely i. vac. The residue is purified bychromatography on silica gel (eluting gradient: petroleum ether/ethylacetate=95:5->80:20)

Yield: 230 mg (14%)

C₁₈H₂₆ClNO₅ (371.86)

Mass spectrum: (M+H)⁺=372/374 (chlorine isotope)

R_(f) value: 0.65 (silica gel; petroleum ether/ethyl acetate=7:3)

(b) ethyl3-chloro-4-[2-(hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoate

Prepared analogously to Example 1g from ethyl442-(tert.-butoxycarbonyl-methoxy)-1-methyl-ethylamino]-3-chloro-benzoateand trifluoroacetic acid in dichloromethane.

Yield: 87%

C₁₄H₁₈ClNO₅ (315.75)

Mass spectrum: (M+H)⁺=316/318

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=9:1)

(c) ethyl 3-chloro-4-(5-methyl-momholin-3-on-4-yl)-benzoate

Prepared analogously to Example 41c from ethyl3-chloro-4-[2-(hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoateand thionyl chloride with DMF in dichloromethane.

Yield: 69% (contaminated)

C₁₄H₁₆ClNO₄ (297.73)

Mass spectrum: (M+H)⁺=298/300 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=19:1)

(d) 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoic acid

Prepared analogously to Example 31b from ethyl3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoate with lithiumhydroxide in THF and water.

Yield: 91%

C₁₂H₁₂ClNO₄ (269.68)

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=9:1)

(e)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoic acid and(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TBTUand TEA in DMF.

Yield: 28%

C₂₂H₂₂Cl₂N₄O₄ (477.34)

Mass spectrum: (M−Hy=475/477/479 (chlorine isotope)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

EXAMPLE 1123-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylamino-pyrrolidin-1-yl)-benzamide

(a) 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile

0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml(0.58 g, 5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF arecombined with 231 mg (5.30 mmol) 55% sodium hydride dispersion atambient temperature with stirring and under an argon atmosphere. Afterstirring at ambient temperature for 3.5 h the reaction mixture is pouredinto water and extracted with ethyl acetate after thorough mixing. Thecombined organic phases are washed with sat. sodium chloride solution,dried over magnesium sulphate and evaporated down completely i. vac.

Yield: 1.11 g (92%)

C₁₃H₁₆ClN₃ (249.74)

Mass spectrum: (M+H)⁺=250/252 (chlorine isotope)

R_(f) value: 0.42 (silica gel; petroleum ether/ethyl acetate=1:1)

(b) 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzoic acid

Prepared analogously to Example 13b from3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile with 10-molarsodium hydroxide solution and ethanol.

Yield: 27%

C₁₃H₁₇ClN₂O₂ (268.74)

Mass spectrum: (M+H)⁺=269/271 (chlorine isotope)

(c)3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylamino-pyrrolidin-1-yl)-benzamide

Prepared analogously to Example 1f from3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzoic acid and(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA inDMF.

Yield: 74%, slightly contaminated

C₂₂H₂₅Cl₂N₅O (446.37)

Mass spectrum: (M+H)⁺=446/448/450 (chlorine isotope)

R_(f) value: 0.65 (silica gel; dichloromethane/methanol=8:2+0.5% conc.ammonia solution)

EXAMPLE 113N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzamide

(a) 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzonitrile

1.00 g (5.29 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile are stirredtogether with 1.35 g (12.0 mmol) potassium-tert.-butoxide in 4 ml DMSOat ambient temperature under an argon atmosphere for 35 min and then1.00 g (8.16 mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO areadded. After stirring at ambient temperature for 68 h the reactionmixture is poured into semisat. sodium chloride solution and extractedwith ethyl acetate. The combined organic phases are dried over magnesiumsulphate and evaporated down completely i. vac.

Yield: 0.58 g (43%)

C₁₁H₈F₃N₃O (255.20)

Mass spectrum: (M+H)⁺=256

R_(f) value: 0.15 (silica gel; dichloromethane+0.5% conc. ammoniasolution)

(b) 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzoic acid

Prepared analogously to Example 13b from3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile with 10-molarsodium hydroxide solution and ethanol.

Yield: 56%

C₁₁H₉F₃N₂O₃ (274.20)

R_(f) value: 0.60 (silica gel; dichloromethane/ethanol=8:2+0.5% aceticacid)

(c)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzamide

Prepared analogously to Example 1f from the4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzoic acid and(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA inDMF.

Yield: 12%, contaminated

C₂₀H₁₇ClF₃N₅O₂*2 CF₃COOH (679.88/451.83)

Mass spectrum: (M+H)⁺=452/454 (chlorine isotope)

R_(f) value: 0.58 (silica gel; dichloromethane/methanol=8:2+0.5% conc.ammonia solution)

EXAMPLE 127N-[(1S)-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) (1S)—N-Boc-147-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine

1.68 g (6.37 mmol) tert.-butyl[1-(2-chloro-acetyl)-3-methyl-butyl]-carbamate in 15 ml of methanol arecombined with 819 mg (6.37 mmol) 2-amino-4-chloro-pyridine at ambienttemperature with stirring and the mixture is refluxed for 3 days. Afterevaporation i. vac. the residue is combined with 5% sodium hydrogencarbonate solution and stirred for 20 h at ambient temperature. Then itis extracted with dichloromethane, the combined organic phases are driedover sodium sulphate and evaporated down completely i. vac. The residueis purified by chromatography on silica gel (eluting gradient:dichloromethane/ethanol=100:0->94:6).

Yield: 180 mg (8%)

C₁₇H₂₄ClN₃O₂ (337.85)

Mass spectrum: (M+H)⁺=338/340 (chlorine isotope)

R_(f) value: 0.61 (silica gel; dichloromethane/ethanol=9:1)

(b) (1S)-147-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine

Prepared analogously to Example 1g from(1S)—N-Boc-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylaminewith trifluoroacetic acid in dichloromethane.

Yield: quant.

C₁₂H₁₆ClN₃*2 CF₃CO₂H (465.78/237.73)

Mass spectrum: (M+H)⁺=238/240 (chlorine isotope)

(c)N-[(1S)-1-(5-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and(1S)-1-(5-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine withTBTU and DIPEA in THF.

Yield: quant.

C₂₄H₂₇ClN₄O₃ (454.95)

Mass spectrum: (M+H)⁺=455/457 (chlorine isotope)

R_(f) value: 0.54 (silica gel; dichloromethane/ethanol=9:1)

The Examples that follow describe the preparation of some pharmaceuticalformulations which contain as active substance any desired compound ofgeneral formula I:

EXAMPLE I

Dry ampoule containing 75 mg of active substance per 10 ml

Composition:

Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0ml

Preparation:

Active substance and mannitol are dissolved in water. After packagingthe solution is freeze-dried. To produce the solution ready for use forinjections, the product is dissolved in water.

EXAMPLE II

Dry ampoule containing 35 mg of active substance per 2 ml

Composition:

Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0ml

Preparation:

Active substance and mannitol are dissolved in water. After packaging,the solution is freeze-dried.

To produce the solution ready for use for injections, the product isdissolved in water.

EXAMPLE III

Tablet containing 50 mg of active substance

Composition:

(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0mg

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side. Diameter of the tablets: 9 mm.

EXAMPLE IV

Tablet containing 350 mg of active substance

Composition:

(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0mg

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side. Diameter of the tablets: 12 mm.

EXAMPLE V

Capsules containing 50 mg of active substance

Composition:

(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powderedlactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg

Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatine capsules in acapsule filling machine.

EXAMPLE VI

Capsules containing 350 mg of active substance

Composition:

(1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3)Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg

Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatine capsules in acapsule filling machine.

EXAMPLE VII

Suppositories containing 100 mg of active substance

1 suppository contains:

Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mgPolyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitanmonostearate 840.0 mg 2,000.0 mg

Preparation:

The polyethyleneglycol is melted together with polyethylenesorbitanmonostearate. At 40° C. the ground active substance is homogeneouslydispersed in the melt. It is cooled to 38° C. and poured into slightlychilled suppository moulds.

1. A compound of the formula

wherein A denotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one anotherdenotes a hydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl,hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group and R^(6b) independently of one anothermay be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl,C₁₋₄-alkyloxycarbonyl or C₁₋₃-alkylsulphonyl group, with the provisothat in the above-mentioned substituted 7-membered groups A theheteroatoms optionally introduced as substituents are not separated fromanother heteroatom by precisely one carbon atom, or a group of theformula

or wherein m denotes the number 1 or 2, X¹ denotes an oxygen atom or amethylene, —NR^(6b)—, carbonyl or sulphonyl group, X² denotes an oxygenatom or a —NR^(6b) group, X³ denotes a methylene, carbonyl or sulphonylgroup, X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonylgroup, X⁵ denotes a carbonyl or sulphonyl group, X⁶ denotes an oxygenatom, a —NR^(6b) or methylene group, X⁷ denotes an oxygen or sulphuratom or a —NR^(6b) group, X⁸ denotes a methylene or carbonyl group, X⁹denotes a —NR^(6b) or carbonyl group, X¹⁰ denotes a sulphinyl orsulphonyl group and R^(6a) independently of one another denote ahydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group and R^(6b) independently of one anothermay be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl,C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso thatin the above-mentioned substituted 7-membered groups A the heteroatomsoptionally introduced as substituents are not separated from anotherheteroatom by precisely one carbon atom, R¹ denotes a hydrogen,fluorine, chlorine or bromine atom, a C₁₋₃-alkyl group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, aC₂₋₃-alkenyl, C₂₋₃-alkynyl, nitro, amino, C₁₋₃-alkoxy, a mono-, di- ortrifluoromethoxy group, R² denotes a hydrogen, fluorine, chlorine orbromine atom or a C₁₋₃-alkyl group, R³ denotes a hydrogen atom, aC₂₋₃-alkenyl or C₂₋₃-alkynyl group or a straight-chain or branchedC₁₋₆-alkyl group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, and which is optionally substituted by anitrile, hydroxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms maybe wholly or partly replaced by fluorine atoms, an allyloxy,propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy,C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyl-oxy,C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino,mercapto, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy,C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl,benzyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl,aminosulphonyl, C₁₋₃-alkylaminosulphonyl,di-(C₁₋₃-alkyl)-aminosulphonyl, C₃₋₆-cycloalkyleneiminosulphonyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₅-alkylcarbonylamino,C₁₋₃-alkylsulphonylamino, N—(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino,C₃₋₆-cycloalkylcarbonylamino, aminocarbonylamino,C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)-aminocarbonylamino, a 4-to 7-membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino,phenylcarbonylamino or guanidino group, a carboxy, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₁₋₄-alkoxycarbonyl,C₄₋₆-cycloalkyleneiminocarbonyl group, a phenyl or heteroaryl,phenylcarbonyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkylgroup which is optionally mono- or polysubstituted in the phenyl orheteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy,mono-, di- or trifluoromethoxy, benzyloxy, carboxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to 7-memberedcycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy, C₁₋₃-alkyloxycarbonylor C₁₋₃-alkyloxy-carbonylamino group, a 3- to 7-membered cycloalkyl,cycloalkyleneimino, cycloalkyl-C₁₋₃-alkyl orcycloalkyleneimino-C₁₋₃-alkyl group wherein in the cyclic moiety amethylene group may be replaced by an —NH— group optionally substitutedby a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group or by an oxygen atom andwherein additionally a methylene group adjacent to the —NH—,—N(C₁₋₃-alkylcarbonyl)— or —N(C₁₋₃-alkyl)- group may be replaced in eachcase by a carbonyl or sulphonyl group, with the proviso that acycloalkyleneimino group as hereinbefore defined wherein two nitrogenatoms are separated from one another by precisely one —CH₂— group isexcluded, R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group or R³ and R⁴together with the carbon atom to which they are bound, denote aC₃₋₇-cycloalkyl group, while one of the methylene groups of theC₃₋₇-cycloalkyl group may be replaced by an imino, C₁₋₃-alkylimino,acylimino or sulphonylimino group, R⁵ denotes a hydrogen atom or aC₁₋₃-alkyl group, B denotes a group of formula

wherein n denotes the number 1 or 2, R⁷ denotes a hydrogen atom or aC₁₋₃-alkyl, hydroxy, C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group and R⁸independently of one another denote a hydrogen, fluorine, chlorine,bromine or iodine atom, a C₁₋₃-alkyl group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl orC₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy, trifluoromethoxy, amino, nitro ornitrile group, while, unless otherwise stated, by the term “heteroarylgroup” mentioned hereinbefore in the definitions is meant a monocyclic5- or 6-membered heteroaryl group, while the 6-membered heteroaryl groupcontains one, two or three nitrogen atoms and the 5-membered heteroarylgroup contains an imino group optionally substituted by a C₁₋₃-alkyl,phenyl or phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or an iminogroup optionally substituted by a C₁₋₃-alkyl, phenyl, amino-C₂₋₃-alkyl,C₁₋₃-alkyl-amino-C₂₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to7-membered cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group oran oxygen or sulphur atom and additionally a nitrogen atom or an iminogroup optionally substituted by a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl groupand two or three nitrogen atoms, and moreover a phenyl ring optionallysubstituted by a fluorine, chlorine or bromine atom, a C₁₋₃-alkyl,hydroxy, C₁₋₃-alkyloxy group, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino or C₃₋₆-cycloalkyleneimino group may be fused tothe above-mentioned monocyclic heteroaryl groups via two adjacent carbonatoms and the bond is effected via a nitrogen atom or a carbon atom ofthe heterocyclic moiety or a fused-on phenyl ring, while the alkyl andalkoxy groups contained in the above-mentioned definitions which havemore than two carbon atoms may, unless otherwise stated, bestraight-chain or branched and the alkyl groups in the previouslymentioned dialkylated groups, for example the dialkylamino groups, maybe identical or different, and the hydrogen atoms of the methyl or ethylgroups contained in the foregoing definitions may be wholly or partlyreplaced by fluorine atoms, or a tautomer or salt thereof.
 2. A compoundof the formula I according to claim 1, wherein A denotes a group of theformula

wherein m denotes the number 1 or 2, R^(6a) independently of one anotherdenote a hydrogen or fluorine atom, a C₁₋₃-alkyl, hydroxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group and R^(6b) independently of one anothermay be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl,C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso thatin the above-mentioned substituted 7-membered groups A the heteroatomsoptionally introduced as substituents are not separated from anotherheteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes a methylene, —NR^(6b)—,carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b)group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ denotesan oxygen or sulphur atom, a —NR^(6b) or carbonyl group, X⁵ denotes acarbonyl or sulphonyl group, X⁸ denotes a carbonyl group, X⁹ denotes acarbonyl group, R^(6a) independently of one another denote a hydrogen orfluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group andR^(6b) independently of one another may be a hydrogen atom, aC₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl orC₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentionedsubstituted 7-membered cyclic groups A the heteroatoms introduced assubstituents are not separated from another heteroatom by precisely onecarbon atom, R¹ denotes a hydrogen, fluorine, chlorine or bromine atom,a C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, a C₂₋₃-alkenyl, C₂₋₃-alkynyl, nitro, amino,C₁₋₃-alkoxy, a mono-, di- or trifluoromethoxy group, R² denotes ahydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl group, R³denotes a C₂₋₃-alkenyl or C₂₋₃-alkynyl group or a straight-chain orbranched C₁₋₆-alkyl group wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, and which is optionally substitutedby a nitrile, hydroxy, a C₁₋₅-alkyloxy group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, an allyloxy,propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy,C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,C₁₋₅-alkyloxy-carbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino,mercapto, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy,C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl,benzyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl,aminosulphonyl, C₁₋₃-alkylaminosulphonyl,di-(C₁₋₃-alkyl)-aminosulphonyl, C₃₋₆-cycloalkyleneiminosulphonyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₅-alkylcarbonylamino,C₁₋₃-alkylsulphonylamino, N—(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino,C₃₋₆-cycloalkylcarbonylamino, aminocarbonylamino,C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)-aminocarbonylamino, a 4-to 7-membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino,phenylcarbonylamino or guanidino group, a carboxy, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₁₋₄-alkoxycarbonyl,C₄₋₆-cycloalkyleneiminocarbonyl group, a phenyl or heteroaryl,phenylcarbonyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkylgroup which is optionally mono- or polysubstituted in the phenyl orheteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy,mono-, di- or trifluoromethoxy, benzyloxy, carboxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to 7-memberedcycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy, C₁₋₃-alkyloxycarbonylor C₁₋₃-alkyloxy-carbonylamino group, a 3- to 7-membered cycloalkyl,cycloalkyleneimino, cycloalkyl-C₁₋₃-alkyl orcycloalkyleneimino-C₁₋₃-alkyl group wherein in the cyclic moiety amethylene group may be replaced by a —NH— group optionally substitutedby a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group or by an oxygen atom andwherein additionally a methylene group adjacent to the —NH—,—N(C₁₋₃-alkylcarbonyl)— or —N(C₁₋₃-alkyl)- group may be replaced in eachcase by a carbonyl or sulphonyl group, with the proviso that acycloalkyleneimino group as hereinbefore defined wherein two nitrogenatoms are separated from one another by precisely one —CH₂— group isexcluded, R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group, R⁵ denotes ahydrogen atom or a C₁₋₃-alkyl group, B denotes a group of the formula

wherein n denotes the number 1 or 2, R⁷ denotes a hydrogen atom, aC₁₋₃-alkyl, hydroxy, C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group and R⁸independently of one another denote a hydrogen, fluorine, chlorine,bromine or iodine atom, a C₁₋₃-alkyl group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl orC₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy, trifluoromethoxy, amino, nitro ornitrile group, while, unless otherwise stated, by the term “heteroarylgroup” mentioned hereinbefore in the definitions is meant a monocyclic5- or 6-membered heteroaryl group, while the 6-membered heteroaryl groupcontains one, two or three nitrogen atoms and the 5-membered heteroarylgroup contains an imino group optionally substituted by a C₁₋₃-alkyl,phenyl or phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or an iminogroup optionally substituted by a C₁₋₃-alkyl, phenyl, amino-C₂₋₃-alkyl,C₁₋₃-alkylamino-C₂₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to7-membered cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group oran oxygen or sulphur atom and additionally a nitrogen atom or an iminogroup optionally substituted by a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl groupand two or three nitrogen atoms, and moreover a phenyl ring optionallysubstituted by a fluorine, chlorine or bromine atom, a C₁₋₃-alkyl,hydroxy, C₁₋₃-alkyloxy group, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino or C₃₋₆-cycloalkyleneimino group may be fused tothe above-mentioned monocyclic heteroaryl groups via two adjacent carbonatoms and the bond is effected via a nitrogen atom or a carbon atom ofthe heterocyclic moiety or a fused-on phenyl ring, while the alkyl andalkoxy groups contained in the above-mentioned definitions which havemore than two carbon atoms may, unless otherwise stated, bestraight-chain or branched and the alkyl groups in the previouslymentioned dialkylated groups, for example the dialkylamino groups, maybe identical or different, and the hydrogen atoms of the methyl or ethylgroups contained in the foregoing definitions may be wholly or partlyreplaced by fluorine atoms, or a tautomer or salt thereof.
 3. A compoundof the formula I according to claim 1, wherein A denotes a group of theformula

wherein m denotes the number 1 or 2, R^(6a) independently of one anotherdenote a hydrogen or fluorine atom, a C₁₋₃-alkyl, hydroxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl orC₁₋₃-alkylcarbonylamino group and R^(6b) independently of one anothermay be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl,C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso thatin the above-mentioned substituted 7-membered groups A the heteroatomsoptionally introduced as substituents are not separated from anotherheteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes a methylene, —NR^(6b)—,carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b)group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ denotesan oxygen or sulphur atom or a —NR^(6b) group, X⁵ denotes a carbonyl orsulphonyl group, R^(6a) independently of one another denote a hydrogenor fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group andR^(6b) independently of one another may be a hydrogen atom, aC₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl orC₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentionedsubstituted 7-membered cyclic groups A the heteroatoms introduced assubstituents are not separated from another heteroatom by precisely onecarbon atom, R¹ denotes a fluorine, chlorine or bromine atom, aC₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, a nitro, C₁₋₃-alkoxy, a mono-, di- ortrifluoromethoxy group, R² denotes a hydrogen atom, R³ denotes astraight-chain or branched C₁₋₆-alkyl group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, and which isoptionally substituted by a nitrile, hydroxy, benzyloxy, a C₁₋₅-alkyloxygroup wherein the hydrogen atoms may be wholly or partly replaced byfluorine atoms, an allyloxy, C₁₋₅-alkylcarbonyloxy,C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino,C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy,C₁₋₃-alkyloxycarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl,aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino ordi-(C₁₋₃-alkyl)-aminocarbonylamino group, an aminocarbonyl,C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, a phenyl or heteroaryl,phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionallymono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine,chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- ortrifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, a 3- to7-membered cycloalkyl group wherein in the cyclic moiety a methylenegroup may be replaced by a —NH— group optionally substituted by aC₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or an oxygen atom, R⁴ denotes ahydrogen atom, R⁵ denotes a hydrogen atom, B denotes a group of theformula

wherein n denotes the number 1, R⁷ denotes a hydrogen atom and R⁸denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, amethyl, C₂₋₃-alkynyl, or methoxy group, wherein the hydrogen atoms maybe wholly or partly replaced by fluorine atoms, while, unless otherwisestated, by the term “heteroaryl group” mentioned hereinbefore in thedefinitions is meant a monocyclic 5- or 6-membered heteroaryl group,while the 6-membered heteroaryl group contains one, two or threenitrogen atoms and the 5-membered heteroaryl group contains an iminogroup optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphuratom or an imino group optionally substituted by a C₁₋₃-alkyl group oran oxygen or sulphur atom and additionally a nitrogen atom or an iminogroup optionally substituted by a C₁₋₃-alkyl group and two or threenitrogen atoms, and the bond is effected via a nitrogen atom or via acarbon atom, while the alkyl and alkoxy groups contained in theabove-mentioned definitions which have more than two carbon atoms may,unless otherwise stated, be straight-chain or branched and the alkylgroups in the previously mentioned dialkylated groups, for example thedialkylamino groups, may be identical or different, and the hydrogenatoms of the methyl or ethyl groups contained in the foregoingdefinitions may be wholly or partly replaced by fluorine atoms, or atautomer or salt thereof.
 4. A compound of the formula I according toclaim 3, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 3 andR³ denotes a straight-chain or branched C₁₋₆-alkyl group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, andwhich is optionally substituted by a nitrile, hydroxy, benzyloxy, aC₁₋₅-alkyloxy group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, an allyloxy, C₁₋₅-alkylcarbonyloxy,C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino,C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy,C₁₋₃-alkyloxycarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl,aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino ordi-(C₁₋₃-alkyl)-aminocarbonylamino group, an aminocarbonyl,C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, while the alkyl and alkoxy groupscontained in the above-mentioned definitions which have more than twocarbon atoms may, unless otherwise stated, be straight-chain or branchedand the alkyl groups in the previously mentioned dialkylated groups, forexample the dialkylamino groups, may be identical or different, and thehydrogen atoms of the methyl or ethyl groups contained in the foregoingdefinitions may be wholly or partly replaced by fluorine atoms, or atautomer or salt thereof.
 5. A compound of the formula I according toclaim 3, wherein A, R¹, R², R⁴, R⁵ are defined as in claim 3 and R³denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl orheteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstitutedin the phenyl or heteroaryl moiety by fluorine, chlorine or bromineatoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, orC₁₋₃-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group whereinin the cyclic moiety a methylene group may be replaced by a —NH— groupoptionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, orby an oxygen atom, while, unless otherwise stated, by the term“heteroaryl group” mentioned hereinbefore in the definitions is meant amonocyclic 5- or 6-membered heteroaryl group, while the 6-memberedheteroaryl group contains one, two or three nitrogen atoms and the5-membered heteroaryl group contains an imino group optionallysubstituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an iminogroup optionally substituted by a C₁₋₃-alkyl group or an oxygen orsulphur atom and additionally a nitrogen atom or an imino groupoptionally substituted by a C₁₋₃-alkyl group and two or three nitrogenatoms, and the bond is effected via a nitrogen atom or via a carbonatom, while the alkyl groups contained in the foregoing definitionswhich have more than two carbon atoms may, unless otherwise stated, bestraight-chain or branched and the alkyl groups in the previouslymentioned dialkylated groups, for example the dialkylamino groups, maybe identical or different, and the hydrogen atoms of the methyl or ethylgroups contained in the foregoing definitions may be wholly or partlyreplaced by fluorine atoms, or a tautomer or salt thereof.
 6. A compoundof the formula I according to claim 1, wherein A denotes a group of theformula

wherein m denotes the number 1 or 2, R^(6a) independently of one anotherdenote a hydrogen or fluorine atom or a C₁₋₃-alkyl group and R^(6b) maybe a hydrogen atom or a C₁₋₃-alkyl group, with the proviso that in theabove-mentioned substituted 7 membered groups A the heteroatomsoptionally introduced as substituents are not separated from anotherheteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes a methylene, —NR^(6b)—,carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b)group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ an oxygenor sulphur atom or a —NR^(6b) group, X⁵ denotes a carbonyl or sulphonylgroup, R^(6a) independently of one another denote a hydrogen or fluorineatom or a C₁₋₃-alkyl group and R^(6b) independently of one another maybe a hydrogen atom or a C₁₋₃-alkyl group, with the proviso that in theabove-mentioned substituted 7-membered cyclic groups A the heteroatomsintroduced as substituents are not separated from another heteroatom byprecisely one carbon atom, R¹ denotes a chlorine or bromine atom, amethyl or methoxy group, wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, or a nitro group, R² denotes ahydrogen atom, R³ denotes a straight-chain or branched C₁₋₄-alkyl groupwherein the hydrogen atoms may be wholly or partly replaced by fluorineatoms, and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxygroup wherein the hydrogen atoms may be wholly or partly replaced byfluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy orC₁₋₃-alkyloxycarbonyl group, a phenyl or heteroaryl, phenyl-C₁₋₃-alkylor heteroaryl-C₁₋₃-alkyl group which is optionally mono- orpolysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorineor bromine atoms, C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- ortrifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, R⁴ denotes ahydrogen atom, R⁵ denotes a hydrogen atom and B denotes a group offormula

wherein n denotes the number 1, R⁷ denotes a hydrogen atom and R⁸denotes a chlorine or bromine atom or the ethynyl group, while, unlessotherwise stated, by the term “heteroaryl group” mentioned hereinbeforein the definitions is meant a monocyclic 5- or 6-membered heteroarylgroup, while the 6-membered heteroaryl group contains one, two or threenitrogen atoms and the 5-membered heteroaryl group contains an iminogroup optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphuratom or an imino group optionally substituted by a C₁₋₃-alkyl group oran oxygen or sulphur atom and additionally a nitrogen atom or an iminogroup optionally substituted by a C₁₋₃-alkyl group and two or threenitrogen atoms, and the bond is effected via a nitrogen atom or via acarbon atom, while the alkyl groups contained in the foregoingdefinitions which have more than two carbon atoms may, unless otherwisestated, be straight-chain or branched and the alkyl groups in thepreviously mentioned dialkylated groups, for example the dialkylaminogroups, may be identical or different, and the hydrogen atoms of themethyl or ethyl groups contained in the foregoing definitions may bewholly or partly replaced by fluorine atoms, or a tautomer or saltthereof.
 7. A compound of the formula I according to claim 6, wherein A,R¹, R², R⁴, R⁵ and B are defined as in claim 6 and R³ denotes astraight-chain or branched C₁₋₄-alkyl group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, and which isoptionally substituted by a hydroxy, a C₁₋₄-alkyloxy group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, aC₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy orC₁₋₃-alkyloxycarbonyl group, while the alkyl and alkoxy groups containedin the above-mentioned definitions which have more than two carbon atomsmay, unless otherwise stated, be straight-chain or branched and thealkyl groups in the previously mentioned dialkylated groups, for examplethe dialkylamino groups, may be identical or different, and the hydrogenatoms of the methyl or ethyl groups contained in the foregoingdefinitions may be wholly or partly replaced by fluorine atoms, or atautomer or salt thereof.
 8. A compound of the formula I according toclaim 6, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 6 andR³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl orheteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstitutedin the phenyl or heteroaryl moiety by fluorine, chlorine or bromineatoms, C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy,carboxy, or C₁₋₃-alkyloxycarbonyl group, a 3- to 7-membered cycloalkylgroup wherein in the cyclic moiety a methylene group may be replaced bya —NH— group optionally substituted by a C₁₋₃-alkyl orC₁₋₃-alkylcarbonyl group, or by an oxygen atom, while, unless otherwisestated, by the term “heteroaryl group” mentioned hereinbefore in thedefinitions is meant a monocyclic 5- or 6-membered heteroaryl group,while the 6-membered heteroaryl group contains one, two or threenitrogen atoms and the 5-membered heteroaryl group contains an iminogroup optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphuratom or an imino group optionally substituted by a C₁₋₃-alkyl group oran oxygen or sulphur atom and additionally a nitrogen atom or an iminogroup optionally substituted by a C₁₋₃-alkyl group and two or threenitrogen atoms, and the bond is effected via a nitrogen atom or via acarbon atom, while the alkyl groups contained in the foregoingdefinitions which have more than two carbon atoms may, unless otherwisestated, be straight-chain or branched and the alkyl groups in thepreviously mentioned dialkylated groups, for example the dialkylaminogroups, may be identical or different, and the hydrogen atoms of themethyl or ethyl groups contained in the foregoing definitions may bewholly or partly replaced by fluorine atoms, or a tautomer or saltthereof.
 9. A compound of the formula I according to claim 1, wherein Adenotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one anotherdenote a hydrogen or fluorine atom or a C₁₋₃-alkyl group, with theproviso that in the above-mentioned substituted 7-membered cyclic groupsA the fluorine atoms introduced as substituents are not separated fromanother heteroatom by precisely one carbon atom, R¹ denotes a chlorineor bromine atom, a methyl or methoxy group, wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, or a nitro group, R²denotes a hydrogen atom, R³ denotes a straight-chain or branchedC₁₋₄-alkyl group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, and which is optionally substituted by ahydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms may be whollyor partly replaced by fluorine atoms, a C₁₋₃-alkylsulphanyl,C₁₋₃-alkylsulphonyl, carboxy or C₁₋₃-alkyloxycarbonyl group, a furanyl,thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C₁₋₂-alkyl orimidazolyl-C₁₋₂-alkyl group which may optionally be substituted in theheteroaryl moiety by one or two C₁₋₃-alkyl groups, C₁₋₃-alkyloxy groups,carboxy or C₁₋₃-alkyloxycarbonyl groups, and R⁴ denotes a hydrogen atom,R⁵ denotes a hydrogen atom and B denotes a group of the formula

wherein n denotes the number 1, R⁷ denotes a hydrogen atom and R⁸denotes a chlorine or bromine atom or an ethynyl group, while, unlessotherwise stated, by the term “heteroaryl group” mentioned hereinbeforein the definitions is meant a monocyclic 5- or 6-membered heteroarylgroup, while the 6-membered heteroaryl group contains one, two or threenitrogen atoms and the 5-membered heteroaryl group contains an iminogroup optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphuratom or an imino group optionally substituted by a C₁₋₃-alkyl group oran oxygen or sulphur atom and additionally a nitrogen atom or an iminogroup optionally substituted by a C₁₋₃-alkyl group and two or threenitrogen atoms, and the bond is effected via a nitrogen atom or via acarbon atom, while the alkyl groups contained in the foregoingdefinitions which have more than two carbon atoms may, unless otherwisestated, be straight-chain or branched and the alkyl groups in thepreviously mentioned dialkylated groups, for example the dialkylaminogroups, may be identical or different, and the hydrogen atoms of themethyl or ethyl groups contained in the foregoing definitions may bewholly or partly replaced by fluorine atoms, or a tautomer or saltthereof.
 10. A compound of the formula I according to claim 9, whereinA, R¹, R², R⁴, R⁵ and B are defined as in claim 9 and R³ denotes astraight-chain or branched C₁₋₄-alkyl group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, and which isoptionally substituted by a hydroxy, a C₁₋₄-alkyloxy group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, aC₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy orC₁₋₃-alkyloxycarbonyl group, while the alkyl and alkoxy groups containedin the above-mentioned definitions which have more than two carbon atomsmay, unless otherwise stated, be straight-chain or branched and thealkyl groups in the previously mentioned dialkylated groups, for examplethe dialkylamino groups, may be identical or different, and the hydrogenatoms of the methyl or ethyl groups contained in the foregoingdefinitions may be wholly or partly replaced by fluorine atoms, or atautomer or salt thereof.
 11. A compound of the formula I according toclaim 9, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 9 anddenote a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl group which may optionallybe substituted in the heteroaryl moiety by one or two C₁₋₃-alkyl groups,wherein the hydrogen atoms may be wholly or partly replaced by fluorineatoms, C₁₋₃-alkyloxy groups, wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, carboxy or C₁₋₃-alkyloxycarbonylgroups, and unless otherwise stated, by the term “heteroaryl group”mentioned hereinbefore in the definitions is meant a monocyclic 5- or6-membered heteroaryl group, while the 6-membered heteroaryl groupcontains one, two or three nitrogen atoms and the 5-membered heteroarylgroup contains an imino group optionally substituted by a C₁₋₃-alkylgroup, an oxygen or sulphur atom or an imino group optionallysubstituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom andadditionally a nitrogen atom or an imino group optionally substituted bya C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond iseffected via a nitrogen atom or via a carbon atom, while the alkylgroups contained in the foregoing definitions which have more than twocarbon atoms may, unless otherwise stated, be straight-chain or branchedand the alkyl groups in the previously mentioned dialkylated groups, forexample the dialkylamino groups, may be identical or different, and thehydrogen atoms of the methyl or ethyl groups contained in the foregoingdefinitions may be wholly or partly replaced by fluorine atoms, or atautomer or salt thereof.
 12. A compound of the formula I according toclaim 1, wherein the group X¹ denotes a methylene group.
 13. A compoundof the formula I according to claim 1, wherein the group X¹ denotes acarbonyl group.
 14. A compound of the formula I according to claim 1,wherein the group X³ denotes a methylene group.
 15. A compound of theformula I according to claim 1 wherein the group X³ denotes a carbonylgroup.
 16. A compound of the formula I according to claim 1, wherein thegroup X⁴ denotes an oxygen atom.
 17. A compound of the formula Iaccording to claim 1, wherein the group B denotes the group


18. A compound of the formula I according to claim 1, wherein the groupB denotes the group


19. A compound of the formula I according to claim 1, wherein the groupB denotes the group


20. A compound of the formula I according to claim 1, wherein the groupR⁸ denotes a chlorine atom.
 21. A compound of the formula I according toclaim 1, wherein the group R⁸ denotes a bromine atom.
 22. A compound ofthe formula I according to claim 1, wherein the group R⁸ denotes anethynyl group.
 23. A compound according to claim 1, having the formulaIa


24. A compound according to claim 1 selected from the group consistingof: (1)4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-benzamide,(2)4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide,(3) (4) (5) (6) (7) (8)4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide,(9)4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide,(10)N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide(11) (12)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,(13)3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,(14) (15) (16) (17) (18) (19) (20) (21) (22) (23)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide,(24) (25) (26) (27) (28) (29) (30) (31) (32)N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide,(33) (34) (35) or a tautomer or salt thereof.
 25. A physiologicallyacceptable salt of a compound according to claim
 1. 26. A pharmaceuticalcomposition comprising a compound according to claim 1, or aphysiologically acceptable salt thereof, together with one or more inertcarriers and/or diluents.
 27. A method for inhibiting factor Xa or arelated serine protease which comprises administering an inhibitoryamount of a compound in accordance with claim 1 or a physiologicallyacceptable salt thereof.